Research
Our goal is to identify the major genetic factors that predispose to autoimmunity in the central nervous system and modulate disease presentation and progression. 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 provides an outstanding opportunity to facilitate progress in the integration of multiple data sources and functional interpretation of physiological and laboratory results. Specifically, our research plan includes:
- Genome wide gene mapping
- Genotype-phenotype and gene-environment correlations in MS
- Genomic and clinical study of MS populations at low and intermediate risk
- Pharmacogenomics
- Gene expression networks in human and experimental neuroinflammation
Research in the laboratory is funded by the National Institute of Health, the National multiple Sclerosis Society, and Nancy Davis Center Without Walls
Genome wide gene mapping
A large body of data indicates that susceptibility and/or resistance to MS is inherited. Understanding these genetic events is key to define the basic underlying etiology of the disease. However, despite intensive long-standing efforts by many research groups across the globe, the knowledge of MS genetics remains incomplete. We believe that the availability of more efficient tools in molecular genetics together with a growing understanding of the landscape structure of the human genome and a powerful MS sample repository provide us with a new experimental paradigm for the deconstruction of this complex biological problem. Together with collaborators in the US and Europe, we have recently completed two large whole genome association studies in MS using Affymetrix and Illumina >500K SNPs platforms. Genome-wide screening for copy number polymorphisms is in progress. These datasets open a new vista of the MS genome. Confirmatory and functional studies of genes of interest are in progress.
Genotype-phenotype and gene-environment correlations in MS
MS is a heterogeneous disorder, embodying a diverse array of symptoms and clinical outcomes. Very little is known about the underlying cause of disease variability in this disorder. Clearly, however, clinical and demographic variables assume critical importance as stratifying elements for genetic studies. Clinical, quantitative MRI, immunologic and demographic data are incorporated into the analysis to directly address the question of heterogeneity in MS.
Genomic and clinical study of MS populations at low and intermediate risk
Based on the understanding that patterns of genomic disequilibrium are shaped by the history of a population, we are studying individuals with MS with origins other than Northern Europe to identify recombination events and characterize minimal genomic regions harboring disease genes. In collaboration with Dr. David Reich (Dept. Genetics, Harvard Medical School), we used a well characterized African-American MS dataset to develop methods that estimate the ancestral origin of disease loci based on the composite genotypes of linked markers, and showed that this approach can accurately infer ancestry states along the genome.
Pharmacogenomics
These experiments represent an effort to understand heterogeneity in drug response in MS. Clinical and MR endpoints are incorporated into the analysis of genetic data to investigate relationships between genomic and transcriptional correlates of the clinical response to treatment. Because MS is a complex disorder and current disease modifying drugs are pleiotropic agents, multi-analytical and integrative strategies are necessary to define therapeutic mechanisms and to identify patients who will benefit the most from these therapies.
Gene expression networks in human and experimental neuroinflammation
We have analyzed the transcriptional signature of IFN response in MS patients and are using network-based approaches to characterize the global properties of ensembles of co-regulated genes. Efforts are underway to characterize the response to therapeutic drugs based on these networks. In another set of experiments, we are dissecting the tissue-specific transcriptional changes underlying experimental autoimmune encephalomyelitis (EAE). This longitudinal atlas of gene expression in EAE will reveal the molecular anatomy of an encephalitogenic immune response.
*Invitation to Students and Postdoctoral Fellows*
NIH-funded post-doctoral positions are available immediately for motivated candidates with background in genetic epidemiology, molecular biology, signaling, EAE/MS immunobiology, stem cell biology, computational biology, and clinical neurology.
Our strategy is to integrate molecular, informatic, statistical, and epidemiological approaches to illuminate fully the genetics of neuroinflammation. The laboratory and clinics provide a nurturing and interactive environment to acquire and develop skills in modern immunogenetics research. Each student or fellow leads a unique project with appropriate mentoring and advice from the senior members of the lab. Lab members participate in stimulating and challenging lab meetings, journal clubs, seminar programs, and specialized courses. We have access to state of the art core facilities, and the superb neuroscience, immunologic and genetic communities at UCSF, as well as a network of national and international collaborators and opportunities to attend and present at national and international meetings, provide an outstanding environment to successfully achieve ambitious research goals and unique opportunities to branch out and develop long-standing scientific relationships. Finally, the city of San Francisco and surroundings offer unequal beauty, culture and diversity. You are invited to contact us at .