报告题目:Integrated Mouse Genetics and Systems Biology to Dissect Huntington’s Disease Pathogenesis
报 告 人：Xiangdong William Yang, M.D., Ph.D.,
Professor,University of California at Los Angeles (UCLA),
Huntington's disease (HD) is the most common autosomal dominant neurodegenerative disorder, and is characterized by motor, cognitive, and psychiatric symptoms, as well as a relentless disease progression till death. HD is caused by a CAG repeat expansion in the Huntingtin gene, however the molecular mechanisms underlying pathogenesis of selective neurodegeneration and clinical symptoms remain poorly understood. Because HD is a monogenetic disorder, it has the advantage that all HD patients are likely to share tractable disease mechanisms, and therapeutics based on such mechanisms should benefit most, if not all HD patients. To uncover such critical disease mechanisms, our laboratory developed a series of mouse genetic models to dissect cellular and molecular pathogenic mechanisms of HD in vivo. Here, I will discuss our studies applying systems biology to study molecular pathogenic networks in HD. We analyzed over 1000 RNA-sequencing and proteomics datasets from an allelic series of murine Huntingtin knockin mouse models with increasing pathogenic CAG-repeat length, and applied Weighted Gene Coexpresion Network Analyses (WGCNA) to define Huntingtin CAG-length dependent gene modules. These modules reveal novel roles of mutant Huntingtin in impairing striatal neuronal identity gene expression, cell death receptor signaling, and regulation of clustered protocadherin gene expression. Finally, our analyses also uncovered an unexpected link between Huntingtin CAG repeat expansion and molecular aging in the brain.
Dr. Xiangdong William Yang is a professor in the Department of Psychiatry & Biobehavioral Sciences and a member of the Center for Neurobehavioral Genetics at the Semel Institute of the University of California at Los Angeles (UCLA). Dr. Yang completed his undergraduate education at Yale University, obtaining combined B.S./M.S. degrees from the Department of Molecular Biophysics & Biochemistry (MB&B) in 1991. He then completed M.D./Ph.D. training at Rockefeller University (Ph.D., 1998) and Weill Medical College of Cornell University (M.D., 2000). He co-invented (with Nathaniel Heintz) a powerful mouse genetic technology to engineer Bacterial Artificial Chromosomes (BACs) and to generate BAC transgenic mice. Dr. Yang’s own laboratory, established at UCLA in 2002, has made significant contributions in the development of novel BAC transgenic mouse models for human neurodegenerative disorders including Huntington’s disease (HD), Huntington's Disease Like 2 (HDL2), Parkinson's disease (PD), and the use of such models to dissect disease mechanisms and identify therapeutic targets. The Yang lab has also applied novel genetic and systems biology approaches to study neuronal cell-type-specific gene expression, and to decipher in vivo protein interaction and transcriptome networks for HD. Finally, the Yang lab studies the role of basal ganglia circuitry in the generation of normal and pathological behaviors. Dr. Yang is a recipient of BRAIN Initiative Award from U.S. National Institutes of Health, Brain Disorder Award from the McKnight Foundation, the Carol Moss Spivak Scholar Award from UCLA Brain Research Institute, and the Leslie Gehry Brenner Prize for Innovation in Science from the Hereditary Disease Foundation.