Neurodegenerative diseases are characterized by inexorable degeneration of post-mitotic neurons and are largely refractory to therapy. One important subset of these diseases, retinitis pigmentosa (RP), affects a terminally differentiated neuronal population, the rod photoreceptor, and leads to blindness. In contrast to the majority of other neurodegenerative diseases, RP is caused by well-characterized single gene defects, and affects an anatomically accessible portion of the nervous system. The central hypothesis in this proposal is that despite differing genetic etiologies, mechanisms of neuronal degeneration converge upon common critical pathways. Identification of such pathways would advance understanding of neuronal homeostasis and is a prerequisite for developing effective therapies. The proposed research will combine two strategies to identify genes promoting photoreceptor death in multiple genetically distinct mouse models of retinal degeneration. The Principal Investigator (PI) has performed preliminary cDNA array experiments in the rd-1 mouse and has generated a working model of molecular events during early photoreceptor death. Using rd-1 as a benchmark model, the PI will: 1) assess whether similar expression patterns occur in three additional, genetically distinct models of RP (the rds mouse, the tulpl mouse and the rhodopsin mutant mouse) and, 2) eliminate, in the rd-1 mouse, selected genes which are overexpressed in rd-1, and correlate the effects upon the rd-1 retinal phenotype and gene expression pattern. The PI has identified three genes [caspase-3, tumor necrosis factor receptor 1 (TNFR1), and early growth response-1 (EGR-1)], as candidates for this approach, and has performed preliminary experiments with caspase-3. By integrating data from both strategies, the PI will be able to establish cause and effect relationships between individual genes that promote photoreceptor apoptosis in one or more models of RP. The training and research undertaken will extend and broaden the candidate's previous training in veterinary medicine, anatomic pathology, and graduate training in molecular genetics of photoreceptor disorders, leading to true scientific independence. Training will be undertaken at the Yale University School of Medicine under the mentorship of Dr. Colin Barnstable, Professor of Neurobiology and Ophthalmology, who is an internationally recognized molecular biologist using mouse models of retinal development and degeneration.
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