Molecular Regulation of Microglia Behavior
Microglia, resident CNS immune cells, are activated in response to both acute and chronic neural injury. When microglia are activated, they may adopt a variety of responses including 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 microglia response pattern will be dominant are not well understood. Our group has been examining the role of a number of pathways in modulating microglia behavior and response patterns. We have focused extensively on specific transcriptional regulators that are 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.
Poly Glutamine Neurodegeneration
Huntington's Disease (HD) is an inherited neurodegenerative disease caused by autosomal dominant transmission of an expanded CAG repeat in the coding region of the huntingtin gene. HD leads to progressive neurodegeneration primarily in the basal ganglia and cortex. Patients develop progressive motor and cognitive dysfunction that eventually leads to early mortality. We employ a mouse model of HD in which the mutant human huntingtin gene has been knocked into the mouse locus. We are studying several hypotheses of disease pathogenesis including the role of the trophic factor insulin like growth factor -1 (IGF-1) and degeneration of axons and myelin in white matter structures of HD mice. We employ a variety of approaches including molecular characterization of IGF-1 signaling, transport and metabolism and light, fluorescent and transmission electron microscopy to study the pathology of white matter in HD mice.
Spinocerebellar Ataxia Type 7
Spinal Cerebellar Ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion within the ataxin-7 gene. The main characteristics of the disorder include ataxia, retinal degeneration and atrophy of the cerebellum and associated brain stem structures. Our research on SCA7 is focused on experiments to evaluate hypothesis that polyglutamine expanded ataxin-7 results in an altered Purkinje cell (PC) environment within the cerebellum. This altered environment specifically affects neurons that are involved in generating postural tone and coordinated movements. 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. To further address the role of non-cell autonomous factors in SCA7 pathogenesis, we are evaluating the role of IGF-1 using similar approaches in SCA7 as in HD. We are also addressing a potential role for myelin pathology in SCA7 and have extensively evaluated the importance of specialized cerebellar glia known as Bergmann glia. 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).