Dept.: Professor, MD/PhD, Department of Neurology
Neuroscience Focus Group:
Research: Molecular Regulation of Microglia Behavior
Microglia, resident CNS immune cells, are activated in response to acute and chronic neural injury. When microglia are activated, they may adopt a neurotoxic response involving the release of inflammatory cytokines and neurotoxic substances or a neuroprotective response that includes the secretion of trophic factors and promotion of tissue repair. The molecular patterns that regulate which response pattern will be dominant are not well understood. We examine molecular pathways that modulate microglia behavior and response patterns. We have focused on specific transcriptional regulators induced by oxidative stress as well as genes known to be involved in the pathogenesis of Alzheimer’s disease and microRNAs with demonstrated roles in modulating the behavior of macrophages. The overarching goal of this research program is to identify potential therapeutic targets that could modify the inflammatory response to neural injury by promoting microglia to adopt the neuroprotective as opposed to neurotoxic pattern of response to neural injury.
Spinocereballar Ataxia Type 7 (SCA7 and Huntington’s Disease (HD) are inherited neurodegenerative disease caused by autosomal dominant transmission of an expanded CAG repeat in the coding region of the ataxin-7 or huntingtin genes. HD leads to progressive neurodegeneration primarily in the basal ganglia and cortex. We employ a mouse model of HD in which the mutant human huntingtin gene has been knocked into the mouse locus to test several hypotheses of disease pathogenesis. The main characteristics of SCA7 include ataxia, retinal degeneration and atrophy of the cerebellum and associated brain stem structures. Our research on SCA7 is focused on experiments to evaluate the hypothesis that polyglutamine expanded ataxin-7 results in an altered Purkinje cell (PC) environment within the cerebellum. The corollary to this hypothesis is that if some or all of the specific components of the altered environment can be corrected, neurological function may improve and neurodegeneration may be prevented in SCA7 patients. Using a conditional knockout model of SCA7, we have identified a number of key cellular players in the pathogenesis of neurodegeneration in SCA7. We are developing approaches to evaluate transcriptional changes in specific cell types employing laser capture micro-dissection (LCM), fluorescence activated cell sorting (FACS), amplification from small quantity RNA samples and next generation sequencing approaches (RNA-seq) to study both disorders.