Grant: $118,206 - National Institutes of Health - Sep. 30, 2009
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Award Description: X-linked spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by CAG/polyglutamine (polyQ) repeat expansions in the human androgen receptor (AR) gene, and is therefore one of nine neurodegenerative disorders that result from polyQ proteins. The goal of our currently funded proposal is to determine the molecular basis of SBMA motor neuron degeneration. The current proposal has four aims: two of these aims (Aim #1 and Aim #3) are focused upon the transcriptional dysregulation in SBMA; one aim (#2) explores the role of cell death pathways in SBMA motor neuron degeneration; and one aim (#4) will identify AR domains involved in mediating or suppressing AR polyQ neurotoxicity. In this administrative supplement, we are requesting additional funds to accelerate two lines of investigation that are being pursued to achieve the goals set out in two of these aims: 1) We propose to determine the basis of autophagy dysfunction in SBMA. This work stems from two recently published studies from our lab, and will rely upon a well-established primary neuron model of AR neurotoxicity. This work will test the hypothesis that an impairment in autophagosome - lysosome fusion underlies the autophagy dysfunction, and will examine the status of lysosome trafficking and localization in neurons. 2) We propose to define AR-regulated genes in motor neurons using a model of androgen-dependent rescue from hypoxia stress. This work builds upon our published study that demonstarted a role for AR normal function in SBMA motor neuron degeneration. This experiment will apply combined microarray expression analysis and ChIP-Seq to identify the AR regulon required for a successful stress response in motor neurons. This administrative supplement request is responsive to NOT-OD-09-056, as supplemental funding will greatly accelerate the pace of these research projects by allowing us to hire a new postdoctoral fellow and to hire a research faculty member. These experiments are well within the scope of the existing R01 project since they stem from studies being pursued to address two existing specific aims. As the experimental systems are set up and studies are ready to go, this work can be accomplished within a time frame of just less than one year.
Project Description: As defined in the Award Description field
Jobs Summary: TBN, Research facultyto perform the AR microarray analysis and ChIP-Seq as this is a rather complicated line of investigation that will require an experienced person. We plan to hire at this level because I wish to establish standing expertise in the area of high throughput sequencing, neurogenomics, and bioinformatics. I expect that 6.0 cal months effort form this person will be sufficient to complete this project within the time frame. TBN, Postdoctoral fellow to carry out the primary neuron culture studies of autophagy dysfunction. This person will spend almost all of his / her time on this project. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 30, 2009. Help expand these official descriptions using the wiki below.