MICROARRAY ANALYSIS OF RETINAL DEGENERATION IN MICE
Principal Investigator: C J Zeiss
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2003-09-30 - 2008-07-31
more information: NIH RePORT
- CREB1/ATF1 activation in photoreceptor degeneration and protectionWilliam A Beltran
Section of Ophthalmology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Invest Ophthalmol Vis Sci 50:5355-63. 2009..Both are activated in response to a wide array of stimuli, including cellular stress. This study was conducted to assess the CREB1/ATF1 pathway in photoreceptor disease and protection...
- Animals as models of age-related macular degeneration: an imperfect measure of the truthC J Zeiss
Yale University School of Medicine, Section of Comparative Medicine, 375 Congress Avenue, New Haven, CT 06520, USA
Vet Pathol 47:396-413. 2010..Finally, the article gives an overview of spontaneous and induced nonhuman primate models and describes relevant mouse models in the context of each pathogenetic mechanism...
- Complement factor H polymorphism in age-related macular degenerationRobert J Klein
Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA
Science 308:385-9. 2005..This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies...
- CNTF induces dose-dependent alterations in retinal morphology in normal and rcd-1 canine retinaCaroline J Zeiss
Section of Comparative Medicine, Yale University School of Medicine, 375 Congress Ave, New Haven, CT 06510, USA
Exp Eye Res 82:395-404. 2006..These changes were more marked in rcd-1 retinas than in wild-type retinas. This implies that the consequences of CNTF treatment may be substantially influenced by the cellular context into which it is introduced...
- Motor deficits and altered striatal gene expression in aphakia (ak) miceBhupinder Singh
Section of Comparative Medicine, Yale University, 375 Congress Ave, New Haven, CT 06519, USA
Brain Res 1185:283-92. 2007..Their striatal gene expression patterns are consistent with dopaminergic denervation, and change over time, despite relatively unaltered motor performance...