BS, Biochemistry 2000, SUNY Plattsburg
abr3f@virginia.edu
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I am a student in the Neuroscience Graduate Program, and have been a member of the Scrable Lab since August of 2000. My general interests include genetics and mechanisms of neurodegenerative disease, with a primary interest in Huntington's Disease. Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by a triad of personality, cognitive and motor impairments that usually presents clinically in adulthood. It is one of a number of neurodegenerative disorders in which the underlying mutation results in a protein with an expanded polyglutamine tract. This tract is located near the amino-terminus of a ubiquitously expressed protein of unknown function called huntingtin. HD brains show a general atrophy, with markedly greater loss of the medium spiny neurons in the striatum and of pyramidal neurons in the deep layers of the cortex. Although the genetic defect causing HD was assigned to chromosome 4 in 1983, and the specific mutation in the huntingtin protein was identified in 1993, the mechanism of this selective neuronal loss is still unknown. The lac operator/repressor system developed in the Scrable lab will allow me to study the function of the huntingtin protein by regulating its expression both temporally and spatially. More specifically, I am generating a regulatable BAC mouse model of HD in which the lac repressor is only active in the striatum or the cortex of the brain. Using this mouse model, I will determine whether mutant huntingtin acts cell-autonomously or cell non-autonomously in the cell types most affected by HD, and try to understand why neurons die specifically in these two brain regions. Currently, we are in the process of replacing the wild-type with the regulatable promoter region in the full-length human huntingtin gene using homologous recombination and BAC technology. In addition to the regulatable BAC HD mouse model, I have generated a huntingtin reporter mouse in which my regulatable huntingtin promoter drives luciferase expression (Fig. 1). This mouse will aid me in identifying substances which up- and down-regulate huntingtin promoter activity, as well as in determining when and to what level huntingtin is turned on in various tissues. Fig 1.
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