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 Profiles Nadav Ahituv, Ph.D. Dr. Ahituv’s research is focused on understanding the role of regulatory sequences in human biology and disease. Through a combination of comparative genomic strategies, regulatory element analysis, human patient samples, and mouse and fish genetic engineering technologies, he is working to elucidate mechanisms whereby genetic variation within these sequences lead to changes in human phenotypes. Dr. Ahituv’s research focuses on three clinically relevant phenotypic categories. The first is monogenic disease, using limb abnormalities, one of the most common forms of human congenital abnormalities (prevalence of 1 in every 500 births), as a model. The second is complex disease, analyzing how nucleotide changes in regulatory sequences contribute to obesity. The third is pharmacogenomics, characterizing how genetic differences in regulatory sequences lead to clinical variation in response to drugs.
Rosemary Akhurst, Ph.D. Dr. Akhurst's research is focused on mouse developmental genetics. Currently, her group is focusing on mapping and cloning genes that regulate haematopoiesis and vascular development in the mouse. This work could ultimately have implications for cardiovascular disease and cancer, in addition to being of intrinsic interest to developmental biology.
Donna Albertson, Ph.D. Dr. Albertson’s research focuses on four general areas: (1) Array technology development, which involved implementation of a suite of technologies and methodologies for production of BAC arrays for measurement of copy number across the entire human and mouse genomes. (2) Study of the underlying mechanisms of genetic instability that promote particular types of genomic alterations (copy number aberration phenotype) in tumors (3) Copy number polymorphisms (segmental duplications) in mouse genomes. Array Comparative Genomic Hybridization (CGH) analyses of mouse genomes have revealed numerous copy number polymorphisms (segmental duplications) among strains and species, as well as lower level differences that allowed the novel use of BAC arrays to map the strain composition of the genomes of inter-specific backcross mice (4) Identification of genomic alterations in oral cancers and pre-cancers. Work is focused on identification of recurrent genomic aberrations in squamous cell carcinoma (SCC) from different oral sites and investigation of field cancerization in patients with multiple SCC. Studies are underway to investigate the use of genomic aberrations as biomarkers to evaluate surgical margins for the presence of tumor cells and for surveillance of fields at risk in patients following treatment for oral cancer or pre-cancer.
Brad Aouizerat,
Ph.D. Dr. Aouizerat’s research focuses on the analysis of sub-populations of disease cohorts who share a more homogenous set of traits, which is assumed to be due to a more restricted subset of potential disease determinants. This approach is currently being employed in his study of genetic risk factors for cardiovascular disease, liver disease, and cancer. He also hypothesizes that seemingly disparate disorders that involve shared organ systems or metabolic pathways may share an overlapping subset of determinants. The identification of these risk factors would be of great importance because it would help to prioritize the study of disease genes (i.e., to study more common determinants first). In addition, the identification of shared determinants would facilitate synergy of complementary knowledge in isolated fields, fueling interdisciplinary research endeavors, and accelerating discovery. Application of this methodology to the discipline of rational drug design would likely decrease potential side effects (e.g., protease inhibitors and cardiovascular disease, lipodystrophy and insulin resistance) and the utility of drugs in seemingly unrelated disease (e.g., statin drugs in both cardiovascular disease and cognitive function in the elderly).
Allan Balmain,
Ph.D., F.R.S.E. Dr. Balmain’s main research interests have been the elucidation of the molecular mechanisms of multistage carcinogenesis, with particular emphasis on mouse models of chemically induced skin tumor development. His strategy has been to identify the sequence of somatic genetic alterations, which are associated with discrete stages of tumorigenesis: initiation, promotion, progression to locally invasive lesions and development of metastases. In each case where a genetic change has been identified, he has attempted to address the question of causality by making extensive use of transgenic or knock-out mice, and to investigate the biological consequences of this genetic change for cell behavior during transformation. Dr. Balmain has developed cell lines from tumors representing each of these stages of carcinogenesis, and in some cases has characterized cells from successive stages of development from the same tumor. These have proved invaluable for studies of the causal genetic and biological changes associated with tumor progression. The results have shown that the kinds of genetic and biological alterations seen in mouse tumors are very similar to what is observed in human malignancies, thus providing strong evidence that the mouse is a uniquely appropriate model for the development of cancer in humans. More recently, a major emphasis has been on the study of genetic predisposition and the relationships between germline predisposition and tumor suppressor genes. He is presently extending his studies on skin carcinogenesis to other mouse model systems for tumor development in the lung, prostate and lymphoid system. His goal for the next few years is to exploit mouse model systems for the identification of genes that are important for cancer susceptibility or cancer progression in human populations, as a route to the discovery of novel diagnostics, new possibilities for prevention, or therapeutics.
Laura Bull, Ph.D. Dr. Bull has generated a mouse carrying a mutation in Fic1, the gene that causes a form of progressive familial intrahepatic cholestasis (PFIC) in humans. She introduced this mutation into three distinct mouse strains (129S1, 129S4, and C57Bl/6) and has evidence of background strain-dependent differences in several aspects of the murine Fic1 homozygous mutant phenotype. She will further characterize these differing phenotypes in the pure strain backgrounds, and in F1 mice, in preparation for mapping modifier genes. Having genetically mapped the LCS1 (Lymphedema-Cholestasis Syndrome) locus to a small region on chromosome 15, Dr. Bull will continue to focus on identification of the underlying mutation(s). She is completing a study comparing clinical, biochemical, and treatment outcome features of PFIC due to mutations in FIC1/ATP8B1 versus those due to mutations in BSEP/ABCB11s among 136 already ascertained patients plus newly recruited subjects with this disease.
Esteban Burchard,
M.D., M.P.H. Dr. Burchard’s research interests center around identifying genetic and biologic risk factors for asthma and asthma severity among U.S. ethnic and racial minority groups. In addition, he is interested in how race and racially specific genetic differences influence disease and response to therapies (pharmacogenetics). He works in collaboration with a multi-disciplinary team, which includes faculty with expertise in genetic epidemiology, biostatistics, clinical asthma, and pulmonary molecular and cell biology and genomics. Using tools from these disciplines, he conducts studies designed to elucidate genetic risk factors for asthma and asthma severity. Dr. Burchard initiated and oversees the Genetics of Asthma in Latino Americans (GALA) Study, which is a multi-center international collaboration including UCSF, Harvard, Harlem Hospital, the University of Puerto Rico and INER of Mexico City. The goal of the GALA Study is to identify genetic risk factors for asthma and asthma severity among Mexicans and Puerto Ricans, the two largest Hispanic groups in the U.S. In addition, Dr. Burchard directs the GREAT Study (Genetic and Environmental Risk Factors in Ethnically Diverse Asthmatic and Therapeutic Groups Study), which is funded by the Sandler Center for Basic Research in Asthma. The goal of the GREAT Study is to identify ethnic specific, pharmacogenetic, and asthma associated genetic risk factors among African Americans. He is also currently helping to develop methods to improve the application of population based genetic studies to ethnically admixed populations, such as African and Latino Americans and apply them to both his previous as well as future patient collections. Finally, Dr. Burchard developed and directs the Study of Pharmacogenetics in Ethnically Diverse Populations (SOPHIE) Study. The SOPHIE Study is the first phase of an ongoing effort to examine genetic variation in diverse racial and ethnic populations in candidate genes proposed to be involved in drug response. The candidate genes that are currently being analyzed code for membrane transporters. The SOPHIE project has established a local cohort of 500 healthy volunteers (ages 8-40 years) recruited from four different racial/ethnic groups (Chinese, African American, Mexican, and Caucasian) in the San Francisco Bay Area.
James
Cleaver, Ph.D. Dr. Cleaver is interested in two areas of research. The first involves the study of factors that influence risk and development of non-melanoma skin cancers that occur in organ transplant patients. The second project focuses on genetic contributions to the risk of human melanoma, its development and progression as well as response to therapy. A broader view of the research conducted in the Cleaver lab includes additional projects focusing on human genetics. The first is a study of Cockayne Syndrome (CS). Cockayne syndrome is a progressive neurodegenerative disorder associated with a DNA repair defect. Two genes CSA and CSB, are specifically involved in the CS disorder, and three other genes, XPB, XPD and XPG give rise to various symptoms of xeroderma pigmentosum (XP), trichothiodystrophy (TTD) and/or CS according to the particular mutations carried by the patients. The genes involved in CS are all linked to nucleotide excision repair (NER) of ultraviolet damage (UV) in transcriptionally active genes (transcription coupled repair, TCR). Cs-a and Cs-b mice have much milder neurological symptoms than human patients, but a greater risk for cancer. Not all the symptoms of CS patients are easily related to repair deficiencies, leading to the hypothesis that there are alternative pathways relevant to the disease particularly those that are downstream consequences of a common defect in the E3 ubiquitin ligase activity, recently associated with the CSA and CSB gene products. Therefore, Dr. Cleaver proposes to examine global and transcription coupled repair in human and mouse fibroblasts and differentiation-associated repair in cells of neuronal origin to identify the contributions of these repair genes in neurodegeneration. He also plans to identify protein targets of CS-dependent ubiquitylation, especially those whose over-expression may have pathological consequences. Finally, Dr. Cleaver will comprehensively analyze the contributions of genetically-determined and drug-induced oxidative damage to mouse neurodegenerative histology, gene expression and behavioral defects to determine the causes and assess therapeutic intervention that may be a model for other more common neurodegenerative disorders such s Alzheimers, Parkinsons and ALS. A second project in the Cleaver lab involves the study of the XP Variant, a human mutator gene for UV damage. The human POLH and POLI genes are paralogs encoding low-fidelity, class Y, DNA polymerases involved in replication of damaged DNA. Mutations are found in POLH in the human disease xeroderma pigmentosum variant (XP-V) which predisposes patients to high risks for sun-induced skin cancers (squamous cell carcinoma and melanoma). The mouse POLI gene contains an inactivating mutation in the mouse 129 strain that is used for making mouse strains through homologous recombination in embryonic stem cells. Dr. Cleaver has successfully targeted POLH in embryonic stem cells to develop a deletion mouse strain and currently has chimeric animals that are being bred to homozygosity. These mice will be used to examine the molecular and genetic changes involved in tumorigenesis, when the process is strongly driven by environmental exposure to solar-simulated light. He intends to complete development and analysis of the mouse strains that are KO and over-expressing transgenic for the POLH gene. As soon as he has a verified KO he will cross it with p53 null, because in vitro experiments show a very strong interaction between the POLH and p53 gene products.
Bruce R. Conklin, M.D. Dr. Conklin’s research focuses on the largest known family of receptors for hormones and drugs, called G protein–coupled receptors (GPCRs). These receptors are encoded by over 700 human genes that are the targets of >40% of all pharmaceuticals. His research utilizes bioinformatics, receptor engineering, and stem cell biology to understand basic pharmacological responses. To best understand GPCR signaling, the Conklin lab has devised several new methods to control G protein signals in vivo, including the development of novel type of receptor used for tissue engineering in multiple tissues called a RASSL (Receptor Activated Solely by a Synthetic Ligand). To test these pathways we use high-throughput experimental methods (functional genomics) in embryonic stem (ES) cells and ES cell-derived cardiac myocytes. More recently we have derived induced pluripotent stem (iPS) cells from patients with human genetic heart rhythm disorders such as Long QT syndrome. These studies should allow us to directly study to role of GPCR signaling in human myocytes with specific human genetic diseases. Dr. Conklin’s interest in pathway-oriented bioinformatics effort has produced a free, publicly distributed software package, GenMAPP (Gene Map Annotator and Pathway Profiler). GenMAPP is now used by researchers world-wide (>15,000 unique registrations, in 35 countries, >400 publications citing the program). We are expanding this open source program to allow genome-wide, pathway-oriented analysis for twenty species, for all types of functional genomic data, such as genetic variation (SNPs), disease association studies, and analysis of functional genomic experiments. Recently the Conklin Lab has helped develop the first public wiki for pathway information.
Lindsey Criswell,
M.D., M.P.H., D.Sc. Dr. Criswell’s research program focuses on the genetics of human autoimmune disease, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). She has recently completed a study of familial clustering of RA disease features and a genome screen focusing on two RA-related quantitative traits utilizing the North American RA Consortium (NARAC) collection of multicase RA families. A genome wide screen using SNP markers has also recently been completed among the NARAC families, in collaboration with Illumina. As part of the Multiple Autoimmune Disease Genetics Consortium (MADGC), Dr. Criswell recently completed a detailed description of the initial 300 multiplex families, including an analysis of a recently discovered autoimmunity gene, PTPN22. A genome wide screen has also recently been completed among the largest of these multiplex autoimmune families, in collaboration with Myriad Genetics. Recent work utilizing the population-based Iowa Women’s Health Study cohort has focused on gene-environment interactions, where she has demonstrated interaction between exposure to tobacco smoke and two specific genetic risk factors. She also recently completed a study of genetic predictors of response to treatment and of infectious complications among a cohort of patients with early RA enrolled in a randomized controlled trial of methotrexate and etanercept (a TNF antagonist). Ongoing candidate gene studies utilizing her large SLE simplex cohort include investigations of several viral receptor loci, CD45, PD1, ESR1, and renin angiotensin system polymorphisms. Dr. Criswell has also recently initiated a comprehensive, family-based study of the HLA region in SLE and RA, using a panel of 2,400 SNP markers across the region and a RA genetics study utilizing an isolated population in the Netherlands. Lastly, Dr. Criswell is collaborating on a study using admixture mapping methods to identify disease loci for SLE among African Americans and an international SLE consortium project to perform a genome wide association study among a large group of Caucasian SLE cases and controls.
Charles Epstein, M.D. Dr. Charles Epstein headed the Division of Medical Genetics in Pediatrics at UCSF and established the UCSF Medical Genetics Clinic in 1967. The clinic is a model for the genetics counseling services now available for patients and their families throughout California and much of the United States. He is on the Executive Committee of the UCSF Institute for Human Genetics, which serves as a unified framework for all human genetics clinical, teaching and research activities at UCSF. The University has recently established a named chair in his honor. Dr. Anthony Wynshaw-Boris is the first Charles J. Epstein Professor in Human Genetics.
Ying-Hui Fu, Ph.D. Dr. Fu studies families with hereditary demyelination in order to understand the cause of Multiple Sclerosis-like phenotypes. One of these, Autosomal Dominant Leukodystrophy (ADLD), mimics the chronic-progressive form of Multiple Sclerosis. Because this is a Mendelian disorder, it is more amenable to molecular characterization than MS where genetic factors are strong but complex. One common theme in her work has been to understand genetically simple (Mendelian) disorders with the hope that such insights will ultimately contribute to the understanding of more complex disorders. This approach will complement the large family collection/whole genome wide linkage analysis approach. Multiple sclerosis is one of the most common disorders of the central nervous system. Clues about myelin biology from rare monogenic disorders of myelin may provide opportunities for novel approaches toward understanding and treating MS. Dr. Fu’s studies include positional cloning and functional characterization of identified mutations. Dr. Fu is also interested in human behavior phenotypes, specifically regulation of human circadian rhythm and sleep homeostasis. Her lab has identified several genes causing extreme early morning lark and other sleep related phenotypes in some families. Identification of the mutations and biochemical analysis, in combination with studies in model organisms, has elucidated many new insights on mammalian circadian regulation. She plans to continue her efforts on unraveling the regulatory mechanisms for these interesting behavioral phenotypes.
Kathleen Giacomini,
Ph.D. Dr. Giacomini’s research is focused on the role of genetic variation in membrane transporters in clinical drug response. In particular, she and her group are identifying genetic variants in membrane transporters in ethnically diverse populations. Cellular studies determining the functional characteristics of the variant transporters are also being performed. Clinical studies are focused on linking variant membrane transporters to variation in clinical drug response including adverse and therapeutic response. Dr. Giacomini's group is particularly focused on transporters in the kidney that are responsible for drug elimination and play a role in drug-induced nephrotoxicities. She is also the principal investigator of the UCSF Pharmacogenetics of Membrane Transporters Program, a large, multi-disciplinary, multi-project effort involving numerous investigators at UCSF, Stanford and Kaiser Permanente in Oakland. She has recently been refunded for another five years on this program, which will continue to be her research focus for the next five years.
Jane Gitschier,
Ph.D. Dr. Gitschier’s laboratory is focused on three areas of research. First, she is clarifying the underlying basis for a fatal neurodegenerative disease formerly called Hallervorden-Spatz Syndrome. In collaboration with Susan Hayflick (OHSU), she discovered that the gene responsible for this inherited disorder encodes pantothenate kinase 2, which catalyzes the first step in the conversion of pantothenate (vitamin B5) to coenzyme A. Moreover, she found that this protein localizes to the mitochondria. Dr. Gitschier plans to elucidate the pantothenate metabolic pathway within the mitochondria, including the question of how pantothenate is transported into the mitochondria. By using a mouse model she generated, she hopes to understand how a defect in this particular pantothenate kinase leads to iron accumulation in the basal ganglia. This model has also shown a retinal degeneration as well as azoospermia, observations she also plan to explore more fully. Second, she is working on discovering the genetic basis for absolute pitch (AP), an uncanny perceptual ability to identify the pitch of a tone without a reference tone. Over the past two years, she has used a website and a national phlebotomy service to collect families with AP, to the point where genetic mapping should be feasible during the ensuing year. Over the next five years, she plans to identify the gene(s) responsible for this trait and to understand how variation in this gene(s) leads to this perceptual trait. An additional aspect of this study has been examination of the perceptual data. This has led to the discovery of a “perceptual magnet” at the musical pitch “A” and the documentation of a perceptual shift in the sharp direction as people age. Over the next five years she plans to further examine these pitch warps. Third, several projects are directed to address the question of genetic vulnerability to environmental mercury toxicity. In one approach, she has tested different inbred strains of mice for variability in sensitivity to ethylmercury and identified one resistant strain so far; over the next five years she plans to map the locus conferring the resistance and eventually to identify the responsible gene. She has also used yeast to dissect the ethylmercury metabolic pathways by assaying deletion strains for sensitivity; she found chromatin and RNA processing pathways to be highly vulnerable. Her future plans include employing micro-arrays to look at a more complete repertoire of genes responding to thimerosal. Finally, she plans to examine the etiology for “pink” disease, an uncommon, severe, neurological reaction to calomel (a mercury salt) in teething powders used in the first part of the twentieth century, hypothesizing that sensitivity to mercury in these individuals has a genetic basis.
Doug Gould, Ph.D. Most common human diseases are complex. Environmental factors are superimposed upon genetic predispositions to determine the presence or absence and severity of disease. Dr. Gould and his colleagues recently identified that mice with mutations in the type IV collagen alpha 1 gene (Col4a1) are predisposed to cerebral hemorrhage (Science 308 (5725), 1167-71 and N Engl J Med. 354 (14), 1489-96). Hemorrhagic stroke is a leading cause of death and the leading cause of long-term disability. They have since identified COL4A1 mutations in human patients with a spectrum of cerebrovascular diseases ranging from porencephaly to cerebral white matter abnormalities. COL4A1 is the major component of basement membranes. Mutations have pleiotropic effects that are dependent on genetic context. Detailed analysis of Col4a1 mutant mice revealed hallmarks of age-related macular degeneration (AMD) including spontaneous choroidal neo-vascularization. AMD is already the leading cause of blindness in the elderly and the prevalence is expected to increase. Despite this, the precise disease mechanisms and location of insult remain unknown. Mouse models of AMD have been difficult to establish reflecting the complexity of the human disease. Col4a1 mutant mice represent a unique and valuable resource for understanding the pathogenic mechanisms of this common and complex blinding disease. The major goals of Dr. Gould's research program are to understand the cellular processes that lead from COL4A1 mutations (and other basement membrane components) to human diseases. He is using multiple approaches to dissect genetic interactions and to test mechanistic hypotheses. Understanding basic disease mechanisms could help people with COL4A1 mutations, and potentially others, reduce the risk of stroke and retain their vision into old age.
Steve Hamilton,
M.D., Ph.D. Dr. Hamilton’s laboratory is occupied with a number of activities involving efforts to identify genetic determinants of psychiatric disorders. First, he is carrying out genome-wide analyses of depression and antidepressant response in a large clinical sample treated with a single antidepressant. Another focus is on collecting canine case-control samples and pedigrees affected with behavioral disorders and conducting genome-wide analyses of these phenotypes. He is also involved in genetic analyses in panic disorder, focusing on the further characterization (SNP fine-mapping and candidate gene sequencing) of genomic regions linked to panic disorder in genome scans. Finally, he is involved in a number of initiatives focusing on the genetics of various behavioral phenotypes such as autism, genetic control of gene expression, high risk depression, and schizophrenia.
Steve
Hauser, M.D. Dr. Hauser’s research focuses on genetic susceptibility to multiple sclerosis. For more than 12 years, Dr. Hauser has been the PI of the Multiple Sclerosis Genetics Group, a consortium of investigators at multiple sites across the US. Two years ago he collaborated on the formation of an international MS consortium (epicenters in SF, Cambridge MA and Cambridge UK) and is now the PI of a large consortium grant on the genetics of MS. Dr. Hauser is internationally known for his research in this area. He plans to continue his efforts to identify informative MS families for linkage studies, collaborate on linkage studies and linkage disequilibrium studies to map genes, and finally larger scale association studies, both candidate genes and genome-wide, to identify MS susceptibility loci.
Wen-Chi Hsueh, Ph.D. Dr. Hsueh’s ongoing research activities focus on the identification of specific genetic influences on aging/longevity, obesity, type 2 diabetes and circadian rhythm through family studies and genetic association studies using large cohorts of unrelated individuals. She plans to establish a new collection(s) of data/specimens for new projects, and collaborate with more investigators for follow-up studies of her current projects. She is currently in discussions with Mexican officials on developing a study on the genetics of type 2 diabetes in the Mexican population. Also, follow-up studies to current projects may involve more thorough statistical/molecular analyses of initial findings, replication studies in other human populations, and in vitro/in-vivo studies.
Y.W. Kan, M.D., F.R.S. Dr. Kan’s current research efforts involve the construction of mouse models for sickle cell anemia that mimic the human variations in the clinical phenotypes in order to provide mice for investigating drugs that inhibit sickling and stimulate fetal hemoglobin expression. Using a transgenic knockout mouse with sickle cell anemia that he previously constructed, he has derived ES cells from the homozygously affected mice and is using homologous recombination to correct the sickle mutation. The ES cells will be differentiated into hematopoietic cells and transplanted for the treatment of sickle mice. He is also exploring gene therapy for alpha-thalassemia using a mouse alpha-thalassemia model that he previously constructed. Finally, he is investigating gene and cell therapy for the treatment of coronary heart disease. He plans to deliver a hypoxia regulated VEGF gene into mouse ischemic hearts using both viral vectors and hematopoietic stem cells. Future work over the next five years will be concentrated on gene and cell therapy for these disorders. While these experiments are performed in mouse models, successful results may lead to their application to human diseases.
Helen Kim, M.P.H., Ph.D. Dr. Kim's research focuses on identifying genetic factors that predispose individuals to stroke and cardiovascular disease. She currently collaborates with a multidisciplinary group of scientists and clinicians at the UCSF Center for Cerebrovascular Research and Kaiser Permanente Division of Research in Oakland on understanding the causes and risk factors for cerebral vascular malformations and occlusive cerebrovascular disease. She is interested in identifying genetic influences on neurological function and patient outcomes after the primary injury from intracranial hemorrhage as well as treatment-related injury from surgical intervention, in patients with aneurysms and other vascular malformations of the brain. She is taking a case-control approach, focusing on genes in key signaling pathways that are necessary for normal development and maintenance of the vascular wall, e.g., matrix metalloproteinase and fibrinolytic, and their interactions. Several case cohorts have been assembled from UCSF and Kaiser, including brain arteriovenous malformation (William L. Young, PI) and subarachnoid hemorrhage (Jonathan Zaroff and Nerissa Ko, PI). She plans on expanding these clinical studies by collecting additional specimens and epidemiologic data, and exploring gene-gene and gene-environment interactions. Additional research interests include investigating approaches for population stratification, multivariate phenotypes, and linkage and admixture mapping. She also regularly participates in the Genetic Analysis Workshop, a collaborative effort among genetic epidemiologists and statistical geneticists to evaluate and compare old and new methods for analyzing complex traits in family data.
Ophir Klein, M.D., Ph.D. Dr. Klein’s research is centered on the processes underlying craniofacial and dental malformations, which are among the most common congenital abnormalities and have profound impacts on the lives of patients and their families. The Klein lab’s main focus is the use of mice as a genetic model system to elucidate the mechanisms responsible for normal and perturbed development of teeth, facial skeleton, taste papillae, and other organs. Specifically, the lab is interested in the role of growth factor signaling and cell-matrix interactions in the formation of orofacial structures and in the regulation of adult stem cells in teeth.
Deanna Kroetz,
Ph.D. Major efforts in the Kroetz laboratory focus on the pharmacogenetics of membrane transporters and cytochrome P450 enzymes. The Genomics Core of the Pharmacogenetics of Membrane Transporters Project at UCSF is currently identifying genetic variation in the coding, untranslated, promoter, and conserved non-coding regions of the multidrug resistance transporter genes. In the near term, she plans to focus on characterizing the functional consequences of non-synonymous variants in these genes using heterologous expression systems and validated transporter assays. The effect of variants in the 5’ and 3’ untranslated regions on mRNA stability and translation will also be studied. Promoter region variants are screened for changes in transcriptional activity and transcription factor binding. Longer-term efforts will involve characterizing the impact of functionally significant variants of these transporters on drug disposition and effect. One example is an ongoing study of the effect of MRP2 promoter region variants with decreased transcriptional activity in-vitro on MRP2 mRNA levels in human livers. Additional collaborative studies will also be carried out in the next five years, including association of genetic variants of multidrug resistance proteins with response to antiretroviral therapy, toxicity and response to taxol in breast cancer, and efficacy of antimalarial drugs in a pediatric population. A second area of interest in the Kroetz laboratory is the metabolism of endogenous fatty acids by cytochrome P450 enzymes into biologically active eicosanoids. Of particular interest is the generation of vasoactive eicosanoids in the renal microvasculature. Multiple variants of the major cytochrome P450 enzymes involved in these reactions have been recently described and several have significant reductions in function. Molecular and pharmacological studies in her laboratory and elsewhere have shown that alteration of these metabolic pathways with chemical inhibitors or genetic disruption influence the control of blood pressure in animal models. She is currently involved in collaborative studies to determine if similar changes in human fatty acid metabolism resulting from genetic variation are associated with blood pressure. A cohort from the INVEST cardiovascular study will be typed for these functionally significant cytochrome P450 polymorphisms and associations between genotype and blood pressure and other measures of cardiac function will be studied.
Miriam
Kuppermann, Ph.D. Dr. Kuppermann’s research focuses on optimizing prenatal testing decision-making in a racially/ethnically diverse Population, evaluation of a decision-assisting tool for prenatal testing, and evaluation of prenatal tests for chromosomal disorder. She is also currently leading a project on intermediate outcomes of hysterectomy and alternatives, a multi-site, multidisciplinary longitudinal study of over 1000 women facing treatment decisions. All of her studies are conducted in racially/ethnically and socio-economically diverse populations, in English, Spanish, and sometimes Chinese (Mandarin and Cantonese). In addition to these specific projects, Dr. Kuppermann is a member of the Steering Committee for the Medical Effectiveness Research Center for Diverse Populations, which brings together investigators from a wide range of disciplines who share an interest in issues related to racial/ethnic and socio-economic health care disparities. She is also an Associate Director of the Reproductive Genetics Research Group, where she collaborates with molecular biologists, clinicians and clinical investigators, and genetic counselors.
Pui-Yan Kwok, M.D.,
Ph.D. Dr. Kwok’s research interests are the use of state-of-the-art strategies to identify genetic factors associated with complex human traits such as longevity, outcome of kidney transplantation, pharmacogenetics of drug response in colon cancer chemotherapy, pharmacokinetics of membrane transporters, and adverse reactions due to cardiovascular medications. In addition, he will be studying the structure-function relationships of DNA sequence variations in the collagen genes and will develop new technologies for single molecule detection for molecular haplotyping. since several of the projects he is initiating are funded for five years, he will be continuing his efforts on them over that period of time. After that, he will likely have new projects studying those and other complex human traits using global approaches with advanced molecular genetic technologies that he and others have been developing.
Carol Mathews, M.D. Dr. Mathews’ research focuses on elucidating the genetic, environmental, and cultural contributions to the development of childhood-onset neurodevelopmental disorders, in particular, Tourette Syndrome (TS), childhood-onset obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder (ADHD), and more recently, other anxiety-related phenotypes. These disorders are common, especially in childhood, they are frequently co-morbid with one another, and there is some evidence that they may have overlapping etiologies. Many of the genetic studies take place in genetically isolated populations, including the Central Valley of Costa Rica (CVCR), and among people of Ashkenazi Jewish descent in the US and Israel. This work is focused on elucidating the phenomenology as it relates to the genetic etiology of the disorder. Clinical studies include studies of pre- and perinatal risk factors for neurodevelopmental disorders, the role of cultural factors in symptom expression, and identification of potential subtypes and/or endophenotypes in order to aid genetic mapping studies. Genetic and genetic epidemiology studies include heritability of specific symptom subtypes and commonly comorbid conditions, candidate gene studies, linkage studies, and genome-wide association studies. Examples of current projects include genetic linkage studies of large, multigenerational families with childhood-onset OCD, clinical studies aimed at identifying potential subtypes of TS using latent class analyses and examining the heritability and transmission patterns of these subtypes, and genomewide association studies of ADHD in the CVCR. Future studies include epidemiology and genetics of obsessive and anxiety disorders in schoolchildren in Costa Rica, and examination of specific candidate genes for OCD.
Walter Miller,
M.D. The Miller laboratory is interested in all areas of human steroidogenesis. He largely centers on three factors, the steroidogenic acute regulatory protein (StAR), cytochrome P450c17 (steroid 17alpha-hydroxylase (17,20 lyase) and P450 oxidoreductase (POR) (each area is currently supported by a separate R01 grant). He has previously made major contributions concerning P450c1a (vitamin D 1alpha-hydroxylase), P450scc (cholesterol side-chain. cleavage enzyme), P450c21 (steroid 21-hydroxylase) and Tenascin-X (an extra cellular matrix protein involved in Ehlers-Danlos Syndrome), including the identification of mutations causing disease, and in the cases of StAR, POR, P450scc, and TNX. Dr. Miller projects that he will make similar, important contributions based on his future work involving the proteins mentioned above.
Robert L. Nussbaum , M.D. Dr. Nussbaum has his research efforts in three main areas. The first is an investigation of the genetic contribution to Parkinson disease (PD). Beginning ten years ago, in collaboration with his colleague Dr. Mihael Polymeropoulos, his group identified the first mendelian-inherited form of PD, a mutation in the gene encoding alpha-synuclein. Since then, he has been working to identify other inherited forms of the disease through family studies. Although inherited forms of PD are rare, the opportunity to discover and understand the pathogenetic mechanisms in rare hereditary forms of the disease gives insight into the pathways and processes that may be involved in the more common, sporadic forms. Dr. Nussbaum is using the information gained from the hereditary forms of the disease to develop disease models in mice using transgenic technology. A second area of research in the Nussbaum lab is a longstanding effort to understand the rare X-linked disease known as the oculocerebrorenal syndrome of Lowe (OCRL), characterized by congenital cataracts, Fanconi syndrome of the renal proximal tubules, neurological dysfunction, and developmental delay. Current treatment is purely symptomatic and palliative. Dr. Nussbaum discovered the gene responsible for OCRL by positional cloning and demonstrated that the gene encodes a phosphatidylinositol (4,5) bisphosphate 5-phosphatase that was shown to be enriched in the trans-Golgi network and early endosomal compartments. The relationship between the enzyme deficiency and the pathophysiological abnormalities in OCRL remain obscure. Surprisingly, mice engineered to lack the OCRL gene have no signs of the disease. Dr. Nussbaum is investigating why mice are protected from a deficiency in this enzyme and how this information might be exploited to expand our understanding of this enigmatic disorder and develop new, specific therapies. Beginning with his arrival at UCSF, Dr. Nussbaum will be starting a translational research effort to assess the value of “Personalized Medicine”, the application of genetic and genomic approaches to improving patient care. Dr. Nussbaum seeks to evaluate if and how genetic and genomic information about an individual, can be used effectively to improve health care by improving outcomes, reducing adverse reactions, lowering costs, and promoting health through risk education. As Chief of the Division of Medical Genetics in the Department of Medicine and as a faculty member in the Institute of Human Genetics, Dr. Nussbaum is seeking to develop collaborative research efforts with clinician-researchers interested in studying how applying genomics can improve patient care.
Jorge Oksenberg,
Ph.D. The principal aim of the Oksenberg laboratory is to identify the major genetic factors that predispose to multiple sclerosis and modulate disease presentation and progression. Neurological impairment in MS is the outcome of a rather extensive and coordinated series of events that include peripheral lymphocyte activation, disruption of the blood-brain barrier, cellular infiltration into the brain parenchyma, and tissue injury. The nature and intensity of this response as well as the physiological ability to restore homeostasis are to a large extent conditioned by the unique amino acid sequences that define allelic variants on each of the participating molecules. Genes, either in their germline configuration and/or as part of complex functional networks, play a primary role in determining who is at risk for developing the disorder, how the disease progresses, and response to therapy. The availability of highly sensitive and high-capacity methods for analysis of gene variation and expression combined with the implementation of algorithms that predict behaviors in complex biological circuits provide an outstanding opportunity to facilitate progress in the integration of multiple data sources and functional interpretation of physiological and laboratory results. More specifically his research plan includes conducting a genome-wide haplotype mapping study of MS families; large family-based and case-control studies of MS candidate regions and genes; genomic and clinical studies of MS populations at low and intermediate risk; the examination of genotype-phenotype correlations in MS; MS pharmacogenomics; investigating gene expression networks in human and experimental neuroinflammation; and genetic studies of experimental autoimmune encephalitis, which is an animal model of the human version of MS. He also intends to continue and/or initiate collaborations with Dr. Jay Levy on immunologic and genetic predictors of antiviral response and disease progression in HIV infection, and with Dr. Catherine Lomen-Hoeth on the genetics of frontotemporal dementia in ALS patients.
Seymour Packman,
M.D. Dr. Packman’s emphasis over the last decade has been on clinical investigation and academic program development. He has maintained a laboratory effort in experimental studies directed towards disease mechanisms in genetic disorders of micronutrient metabolism and transport. His current focus on mechanisms of toxicity in the organic acidemias is derived from his clinical studies of ambiguities in the relationship of treatment to outcome in cobalamin (Cbl) C methylmalonic aciademia; of the effects of liver transplant in Cbl B methylmalonic aciademia; and of a unique subset of patients with primary systemic carnitine deficiency. These clinical investigations were performed under the auspices of the Neurometabolic Program and Clinics, which Dr. Packman and his colleagues developed at UCSF to, specifically, foster research and education in inborn errors. In this context, they are currently addressing mechanism of cellular transport of methylmalonic acid, as a paradigmatic and clinically relevant organic anion; and undertaking molecular and functional studies of cellular carnitine transport. He is conducting the transport work in collaboration with Dr Kathleen Giacomini and her colleagues.
Katherine S. Pollard, Ph.D. The Pollard lab develops statistical and computational methods for the analysis of massive genomic datasets. We are interested in the mode and tempo of genome evolution, in particular sequences that differ significantly between or within species and their relationship to biomedical traits of interest. One of our general aims is to identify specific DNA alterations that are responsible for variation in gene expression. Current projects focus on two major areas: (1) fast evolving regions of the primate genome and (2) adaptive evolution in metagenomic microbial communities. In both projects we develop and apply probabilistic models of molecular evolution to detect sequences that evolve uniquely in one lineage (clade, species or sub-population). Many of these sequences are non-coding elements, such as regulatory signals, structural sites, and RNA genes. We use statistical modeling, bioinformatics, and experimental validation to link changes in these lineage-specific elements to alterations in biological function.
Daniel Pinkel, Ph.D. Dr. Pinkel’s focus, in conjunction with Dr. Donna Albertson, will be to work to translate their array CGH capability, which is now offered to academic investigators through a research core facility, a clinical test provided through the new clinical lab facility at China Basin. Translation will require defining the types of tests that will be offered, the content of the array, analytical, interpretive, and quality control procedures, and so on. It is expected that this effort will involve a number of people, many of which are be members of the Institute for Human Genetics. During the next five years, he will be participating in substantial clinical applications of the technology and continuing development of high-resolution technologies to study genomic and genetic problems.
Louis Ptacek, M.D. Dr. Ptacek’s research focuses on the genetics of neurological disorders ranging from movement disorders to epilepsy and migraine syndromes to sleep cycle disorders. His strategy is to identify Mendelian forms of disease and clone the genes involved as well as characterize their phenotypic spectrum. His work particularly focuses on the genetics of ion channel genes and their role in disease. He has identified such genes underlying Andersen-Tawil syndrome, type 2 cerebral cavernous malformation, familial hemiplegic migraine, paroxysmal non-kinesigenic dyskinesia, familial adult myoclonic epilepsy and various periodic paralyses.
Jennifer Puck, M.D. Dr. Puck’s program focuses on human primary immunodeficiencies, diseases that are pleiotropic in phenotype and rare, but treatable. They are important because they illuminate generalizable mechanisms in human host defenses and autoimmunity that often differ from predictions based on targeted gene disruptions in mice. Projects include investigation of genetics, clinical and molecular characterization, and management of selected primary immunodeficiencies. Studies in humans are augmented with mouse models to advance basic understanding and develop therapies, including hematopoietic stem cell gene therapy. Documentation and scoring of clinical features of selected diseases has been a starting point for experiments to probe linkage and underlying molecular mechanisms. The overarching goal is to return to the clinic with new approaches for population screening, specific diagnosis, identification of genetic modifiers, and treatment.
J. Eduardo Rame, M.D., M. Phil. Dr. Rame’s overall research goal is to understand the inter-individual variability in cardiovascular phenotypes that predispose humans to congestive heart failure (CHF). Dr. Rame and colleagues have an active research program funded by the American Heart Association that has a primary aim of identifying individuals with hypertensive heart disease that are likely to progress to congestive heart failure. One of the specific aims of this project is to investigate genetic susceptibility to adverse left ventricular hypertrophic remodeling in the setting of increased systemic afterload associated with hypertension.
Katherine Rauen, M.D., Ph.D. Dr. Rauen has two main research programs. One involves an exciting class of medical genetic syndromes which has recently emerged caused by germline mutations in genes associated with the Ras/mitogen-activated protein kinase (MAPK) pathway. The research program involves the clinical and basic science study of cancer syndromes with efforts to identify underlying genetic abnormalities affecting common developmental and cancer pathways. Two syndromes are focused upon: Costello syndrome (CS) and cardio-facio-cutaneous (CFC) syndrome. CS is a complex developmental disorder involving characteristic craniofacial features, failure to thrive, developmental delay, cardiac and skeletal anomalies and a predisposition to develop neoplasia, both benign and malignant. CS is caused by activating germline mutations in HRAS. Ras is a critical signaling hub in the cell and is activated by receptor tyrosine kinases, G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. The downstream effectors of Ras are many and control vital cellular functions including cell cycle progression, cell survival, motility, transcription, translation and membrane trafficking. CFC syndrome is a rare multiple congenital anomaly disorder, is caused by germline mutations in BRAF, MEK1 and MEK2 within the MAPK pathway, a downstream cascade affected by Ras. The type of BRAF mutations found in CFC recapitulates the different types of mutations found in cancer which cause an alteration of signaling down the MAPK pathway. However, in contrast to the mutation spectrum seen in cancer, the majority of BRAF mutations identified in CFC in Dr Rauen’s lab are novel. Understanding the genetic role of HRAS in CS and BRAF, MEK1 and MEK2 in CFC syndrome is the first step in gaining insight to the role Ras and Raf plays in human development, cellular signaling and cancer pathogenesis. The second research program involves the application of array CGH in clinical genetics. Gene discovery efforts and genetic pathogenesis utilizing array CGH are ongoing projects in the laboratory.
Jeremy Reiter, M.D., Ph.D. Eukaryotic cilia and flagella are cellular structures familiar to school children everywhere for the elegant swath they cut as they propel protozoa through pond water. Less well recognized is the fact that a single immotile cilium is present on almost every type of vertebrate cell. It is now becoming clear that the primary cilium plays important roles in both development and disease. Primary cilia have roles in sensing environmental information. Photoreceptors and odorant receptors function on primary cilia, and primary cilia are essential for sound reception. Therefore, it is not much of an exaggeration to say that we see, smell and hear through cilia. Our work suggests that cilia also function as critical mediators of intercellular signals during development. One crucial role is in the coordination of the Hedgehog signal transduction pathway. Hedgehog signals are essential regulators of embryonic patterning and cell proliferation, and defects in Hedgehog signaling are important causes of both birth defects and many cancers. This work has begun to suggest that the primary cilium is an organelle dedicated to signal transduction, somewhat analogous to a cellular antenna. We hope that our current endeavors will reveal how this antenna interprets the signals required for normal development and homeostasis, and how malfunctions in the antenna contribute to cancer and other important human diseases. Dr. Reiter's new lab is located at Mission Bay.
Neil Risch, Ph.D. Dr. Risch, a statistical geneticist and genetic epidemiologist, is involved in a variety of projects of both a theoretical and applied nature. These studies include both clinical and population genetic projects. For example, one study involves identification of genes underlying the torsion dystonias. To date, Dr. Risch and his collaborators have identified several genes for specific subtypes of idiopathic dystonia. Yet a number of variant forms remain unmapped. Current research involves additional mapping and positional cloning of these variant forms. Dr. Risch has also been involved in large, multi-site collaborative projects on genetic susceptibility to hypertension and cardiovascular disease endpoints (the NHLBI funded Family Blood Pressure Program, and the Reynolds Foundation funded Heart, Health and Heredity study). These projects involve linkage analysis, positional cloning, and population based association studies. One of these studies recently led to the identification of regions on chromosomes 6 and 21 by admixture linkage disequilibrium analysis in African American subjects with hypertension. Over the next several years, he plans to expand the admixture studies to other cardiovascular and metabolic phenotypes in both African American and Hispanic study subjects. Dr. Risch also has a longstanding collaborative project underway, with Canadian colleagues, on genetic susceptibility to multiple sclerosis. These studies involve both genetic and environmental hypotheses. In the genetics realm, he plans to continue linkage and positional cloning projects on over 1,000 multi-case families, plus undertake new candidate gene studies as well as linkage disequilibrium approaches. A major focus will continue on examination of genetic contributions of the HLA region. He also plans to continue his population genetic studies, examining the relationship between genetic variation and social categorizations such as race and ethnicity, and the importance of these relationships for identifying genetic factors underlying common and complex diseases, as well as rarer, Mendelian forms. He also plans to continue his collaborative efforts with Drs. Kathleen Giacomini at UCSF and Catherine Schaefer at Kaiser Division of Research in Oakland on pharmacogenetics of membrane transporters, and specifically their role in response to antidepressant medications.
Saunak Sen, Ph.D., M.S. Dr. Sen's research centers on statistical design and methods for
Elliott Sherr M.D., Ph.D. Dr. Sherr’s lab studies the genetics of autism and epilepsy, both as a means to better understand normal brain function and to work toward novel therapies. For autism, we study patients and animal models for which there is a disruption of cerebral connectivity, the most common example of this being agenesis or absence of the corpus callosum. The corpus callosum is the largest white matter tract in the brain, with 200 million axons. It is absent in a significant subset of patients with autistic features, exemplified by Kim Peek, whose life was fictionalized in the movie, Rain Man. Dr. Sherr's lab is using linkage analysis, candidate gene, and CNV discovery approaches, coupled with careful clinical and imaging phenotyping, to identify ACC genes for further analysis in forward genetics using mouse models. They are also conducting reverse genetics in mice, as absence of the corpus callosum in these models is also associated with autistic-like behaviors. In a separate line of investigation, Dr. Sherr is studying the causes of severe childhood epilepsies, infantile spasms, Lennox Gastaut and epileptic encephalopathies, using similar genetic approaches.
Ann Slavotinek,
M.D., Ph.D. Dr. Slavotinek’s primary research interest is to investigate the molecular genetic etiology of congenital diaphragmatic hernia (CDH) in humans. This common birth defect is associated with significant perinatal mortality and long-term morbidity. Mutations have been demonstrated in several different genes in syndromic CDH, but the pathogenesis of non-syndromic CDH in humans is unknown. She is currently using several novel approaches for gene identification in CDH, including array comparative genomic hybridization (array CGH), to identify submicroscopic chromosome aberrations in patients who have CDH and additional malformations. She currently has findings in four patients; she plans to use these subjects to identify genes that are important in the pathogenesis of CDH. In these four cases, array CGH has shown genomic clones with reduced copy number suggestive of chromosome deletions, and submicroscopic deletions of three different chromosome regions have been verified using fluorescence in-situ hybridization (FISH) and microsatellite marker analysis. Thus, haploinsufficiency or altered expression of genes contained within the submicroscopic deletions is likely the cause of the CDH and mutations resulting in a loss of function of the same genes could also cause other cases of CDH. She plans to use FISH and microsatellite marker analysis to identify additional patients with submicroscopic chromosome deletions in these chromosome regions and to define the critical regions and eventually the genes associated with the CDH phenotype. She also plans to collect clinical data on affected patients so that a phenotype-genotype relationship for CDH can be established to improve counseling and prognostic information available for families. Over the subsequent five years she plans to identify and screen candidate genes for CDH by direct sequencing of genes in the critical deleted regions at chromosome 3q26, 15q26-15qter and 8p22-8p23 in patients with CDH who have no evidence of a deletion. Upon identification of pathogenic genes, she plans to investigate the relationship between the diaphragmatic defects and other phenotypic anomalies by making an animal model heterozygous and/or homozygous for a null allele of this gene.
Jun S. Song, Ph.D. Dr. Song’s research utilizes integrative genomics to study genetic and epigenetic regulation of eukaryotic gene expression. He develops computational and experimental methods for investigating genetic networks of cell lineage-specific transcription factors and non-coding RNAs. Recent advances in genomics have emphasized the need to go beyond the information contained in the DNA sequence to understand how cell type-specific transcriptional programs are established and maintained. Dr. Song studies how chromatin structure and other epigenetic factors establish spatiotemporal regulation of genes underlying normal cellular physiology and malignant transformation of cells in humans.In particular, his lab develops statistical and probabilistic methods for analyzing high-throughput genomic data and extracting biologically meaningful and relevant information from complex datasets. His main emphasis has been on cancer, but he is also interested in neurodevelopmental and neurodegenerative diseases. His other research interests include mobile DNA elements and the evolution of the human genome.
Deepak Srivastava, M.D. Dr. Srivastava's laboratory focuses on understanding the causes of heart disease and on using knowledge of cardiac developmental pathways to devise novel therapeutics for human cardiac disorders. Specifically, we study the molecular events regulating early and late developmental decisions that instruct progenitor cells to adopt a cardiac cell fate and subsequently fashion a functioning heart. We seek ways to use these pathways to prevent congenital defects and treat acquired heart disease. We also seek to identify the causes of human cardiovascular disease by applying modern genetic technologies for the study of complex traits.
Christian Vaisse,
M.D., Ph.D. The overall goal of research in the Vaisse laboratory is to identify genetic defects implicated in the onset and progression of multifactorial metabolic diseases such as obesity and diabetes. His strategy combines human genetic approaches with molecular biology and animal studies. He is currently concentrating his research on the molecular mechanisms implicated in the hypothalamic effects of the adipocyte secreted, weight-regulating hormone, leptin. After describing the first leptin receptor mutation in severely obese humans, he recently found that genetic alterations in the Melanocortin 4 receptor (MC4R), a mediator of the hypothalamic effects of leptin, are responsible for a more common form of human obesity. Using large scale automated screening procedures he is further investigating the frequency of mutations in the MC4R gene in large cohorts of obese patients. In parallel he is also searching for obesity-causing mutations in additional candidate genes downstream of the leptin pathway. Finally, both through in vitro and in vivo studies he is aiming to understand how these mutations cause obesity and what the implications are for the treatment of this condition. He plans to build a cohort of a 1000 severely obese children and adults who will be screened for mutations in obesity causing genes and be enrolled in therapeutic trials according to their genotypes; determine the prevalence, natural history and pathophysiology of childhood obesity associated with melanocortin-4 receptor mutations; determine the prevalence and mechanism of obesity associated with pro-opiomelanocortin and agouti related protein mutations; determine the prevalence and mechanism of obesity associated with mutations in Sim1, ARNT2 as well as the transcriptional targets of these genes; develop tools to discover tissue specific trans-factors implicated in the splicing of the leptin receptor; and develop a transgenic mouse model, allowing for temporal control of gene expression in the MC4R expressing neurons.
Jeff Wall, Ph.D. Dr. Wall received his PhD in Evolutionary Biology from the University of Chicago and trained as a postdoc both there and at Harvard University. Before joining the faculty at UCSF in 2007, he spent 3 years as a faculty member in the Department of Molecular and Computational Biology at USC. His research spans a wide range of topics in evolutionary and human genetics, including models of speciation, inference of population history from sequence polymorphism data, and analyses of whole genome association study data in admixed populations.
Lauren Weiss, Ph.D. Dr. Weiss' laboratory is also using cell culture models to test functional effects of risk loci using neural stem cells. They will first identify the effects of genetic risk variants and then be able to ascertain whether the effects of genetic risk can be modified at the cellular level by environmental or pharmacological agents. In the long term, one of Dr. Weiss' primary goals is building a collaborative autism research sample with rich phenotypic data in order to utilize genetic information to identify biological subsets of autism, enhance assessment of autism risk, and improve prediction of treatment effectiveness.
Raymond White, Ph.D. Dr. White’s research focuses on characterizing genetic contributions to alcoholism. He is taking a candidate gene approach. Excellent candidates come from several sources. For example, cell and molecular biology experiments have identified a number of very intriguing candidates based on their role in cell signaling in response to alcohol. Based primarily on experiments with cells in culture, variants in the genes that encode the enzymes and regulatory proteins of the cyclic-AMP and PKA axis would be expected to alter neuronal responses to alcohol. Also, gene variants discovered in mouse and other animal models provide a rational basis for human studies of the same genes. Dr. White plans to sequence the exons and regulatory regions of a select group of candidate genes in DNA samples from about 300 individuals who have been characterized in terms of response to an alcohol challenge as members of a cohort developed by Dr. Marc Schuckit. Sequence variants are identified and potential functional consequences determined by in vitro analysis. For follow up, Dr. White plans to study a comparable group of 300 subjects characterized in a similar fashion. However, because many of the functional variants discovered are likely to be rare, he also plans family studies to obtain as many relatives of mutation carriers as possible to determine in a statistically rigorous fashion the relationship between any identified mutation and alcohol phenotypes.
Joseph Wiemels, Ph.D. Dr. Wiemels’s research focuses on determining the causal origin of genetic aberrations in cancer. He is doing this through several approaches: bioinformatic analysis of DNA sequence and structure at the genetic aberration (collaborations with Ru-Fang Yeh and Mark Segal); molecular epidemiology of metabolically critical genes in case-control studies using molecularly defined subsets of cancers; the laboratory study of DNA and chromatin structure in the vicinity of the aberrations, and finally the epidemiologic association of genetically-defined tumor genetic subgroups with putative cancer risk factors. This work involves epidemiologic, toxicological, and molecular biological approaches. He has also initiated array-CGH studies in collaboration with Donna Albertson (UCSF Cancer Center) and NimbleGen Corporation (Madison, WI) to define and characterize the etiology of secondary rearrangements in leukemia. His research interests also include genetic and environmental susceptibility to childhood leukemia. For example, he is exploring folic acid metabolism, xenobiotic metabolism, and membrane transporters as potential contributors. Dr. Wiemels plans to undertake studies to establish the timing of the formation of chromosomal translocations and deletions in childhood leukemia, their origin and determining their mechanism of formation. He also plans studies, in collaboration with Drs. Margaret Wrensch and John Wiencke, on the role of the immune system on the risk of adult brain cancer. This research is borne out of prior observations that allergies are reported less frequently among brain tumor patients when compared to controls. He plans to study the genetic basis of the allergic phenotype by genotyping polymorphisms in immune-related genes such as cytokines and chemokines and their receptors. Longer-term plans also include multi-center genetic epidemiologic studies of brain cancer and meningioma.
John Wiencke, Ph.D. During the upcoming year Dr. Wiencke will commence a second phase of enrollment of ethnic minority lung cancer cases and controls in the SF Bay Area Lung Cancer Study. He will also begin large-scale genotyping studies of existing cases and controls to examine chromosomal regions of interest in mapping lung cancer susceptibility genes. He is currently involved in two long-term initiatives to enlarge etiologic studies of brain tumors in California and nationwide. These proposals have been submitted and are being revised and resubmitted. He is a Co-PI on a grant being resubmitted for a statewide Childhood Brain Tumor Study that will include tumor biology, germline genetics, environmental and nutritional epidemiology. The overall PI of this program project is Dr. Buffler at UCB and Dr. Paul Fisher of Stanford Pediatric Oncology, and USC investigators McKean and Preston Martin. He is also a Co-investigator in a US consortium on the Molecular Epidemiology of Meningioma. The PI for this study is Dr. Elizabeth Claus at Yale. As co-director of the Division of Neuroepidemiogy, his new research efforts will focus on the etiologic aspects of neurological malignancy and other areas of neurological research related to neurosurgery.
John Witte, Ph.D. Dr. Witte’s research constitutes applied and methodologic genetic epidemiology, with the overall aim of deciphering the mechanisms underlying complex diseases. At present, his applied work is primarily focused on prostate cancer, while much of his methodologic work is on association studies and hierarchical modeling. Dr. Witte initiated a series of prostate cancer genetic epidemiology studies, which have had numerous successes toward sorting out the genetic basis of this disease. These include findings from searches across the human genome and from work on specific candidate genes. In particular, using a combination of genome-wide scan, allelic imbalance, and association studies, Dr. Witte and colleagues have isolated distinct chromosomal regions that appear to harbor genes that cause prostate cancer.
Margaret R. Wrensch, M.P.H., Ph.D. Dr. Wrensch’s research focuses primarily on the genetic epidemiology of brain malignancies and on other cancer phenotypes. Projects planned involve the study of genetic, serologic, demographic, and other risk factors for adult glioma and glioma survival in the context of a population based case-control study. She recently received funding to study lung cancer in African American and Latinos in the San Francisco Bay Area examining the role of gene-environment interactions in disease susceptibility and progression. Her longer term plans include a population based case-control study of meningioma etiology and a population based case-control study of childhood brain tumors. These projects will include the study of candidate genes for both types of tumors as well as important environmental covariates and their interactions.
Anthony Wynshaw-Boris, M.D., Ph.D. Dr. Wynshaw-Boris’s research program focuses on understanding the genetic and biochemical pathways required for normal development and human genetic developmental diseases, primarily on pathways important for neurological development and neurogenetic diseases. A major approach in his laboratory is to produce and deploy mouse models to determine the specific in vivo requirements for pathways during development, and to utilize sophisticated genetic, genomic, cell biological and biochemical tools to dissect these pathways in the developing animal. For many years, his laboratory has studied mouse models of the human neuronal migration defects isolated lissencephaly sequence and Miller-Dieker syndrome as well as mouse mutants for each of three Dishevelled genes. These studies have provided important insights into the genetic factors and molecular mechanisms associated with neurological diseases. Recently, his laboratory, as part of an Autism Center of Excellence, is examining genetic causes of brain overgrowth in autism spectrum disorders.
Elad Ziv, M.D. Dr. Ziv’s research focuses on understanding genetic susceptibility to common diseases using admixed populations. In particular, he is interested in using admixed populations to identify genetic variants and gene-environment interactions that underlie susceptibility to common malignancies. His current work focuses on breast cancer. He plans to have several projects underway including a study to determine whether ancestry is a risk factor for breast cancer among Latinas and a related project to examine mammographic density, a strong risk factor for breast cancer, among Latinas. The Latinas in this project are of Mexican ancestry. He also plans to pursue a more ambitious whole genome admixture mapping approach for breast cancer and breast cancer related phenotypes in admixed populations. He is also planning a pharmacogenetic study of tamoxifen, one of the most commonly used drugs for treatment of breast cancer. In addition, he plans to expand his studies of breast cancer to other populations, including African Americans and potentially Latino/Hispanic populations with more prominent African ancestry (Puerto Ricans, Cubans), in contrast to the Mexican subjects he is currently studying. He also plans to participate in a consortium studying the genetics of aging across several large cohorts using a candidate gene approach based on translation of research on aging from animal models, particularly mouse models
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