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Cellular and Molecular Mechanisms Regulating Photoreceptor Morphology

调节光感受器形态的细胞和分子机制

基本信息

批准号：
7888515
负责人：
ABIGAIL M JENSEN
金额：
$ 39.03万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888515
关键词：
Affect Binding Binding Sites Blindness Cell physiology Cells Chemicals Co-Immunoprecipitations Complex Data Defect Development Disease Dominant-Negative Mutation Drosophila genus EGF gene Embryo Extracellular Domain Eye Genes Genetic Goals Homologous Gene Human Immunohistochemistry Knowledge Leber&apos s amaurosis Light Link Macular degeneration Messenger RNA Methods Molecular Morphogenesis Morphology Mus Mutation Neuroglia Orthologous Gene PDZ protein Pathway interactions Phenotype Phosphotransferases Photoreceptors Play Process Proteins Research Retina Retinitis Pigmentosa Role Severities Signal Transduction Signaling Protein Staging System Testing Transgenic Organisms Transmembrane Domain Vertebrate Photoreceptors Yeasts Zebrafish early onset inherited retinal degeneration insight loss of function mutant photoreceptor degeneration protein function public health relevance research study retinal rods rho GTP-Binding Proteins rhophilin tool yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): Photoreceptors are the primary cells that respond to light and transduce it into a chemical signal and are the cells affected in photoreceptor degeneration diseases, including macular degeneration, retinitis pigmentosa (RP) and other inherited retinal degenerations. Although mutations in many genes have been identified that are associated with photoreceptor degeneration diseases, we still know very little about why these mutations cause photoreceptors to die. This proposal seeks to expand our understanding of how vertebrate photoreceptors attain and maintain their unique functional morphology and relationship between photoreceptor morphology and survival. We have shown that the FERM domain containing protein Mosaic eyes (Moe) is an important regulator of Crumbs protein function, directly interacts with Crumbs proteins and also showed that rod photoreceptors that lack moe function have outer segments that are larger than normal. To my knowledge this is the first example of loss-of-function of a gene that results in a larger than normal outer segment instead of a smaller one. Mutations in the human CRUMBS HOMOLOGUE 1 (CRB1) are associated with two vision-loss diseases, Leber's congenital amaurosis and retinitis pigmentosa 12. The severity and early onset of these diseases suggest that CRB1 function is critical for early stages of photoreceptor development and suggest that understanding the role of CRB1 and related proteins in photoreceptors may give us insight into ways to treat LCA and RP12. Photoreceptors in mice lacking Crb1 function have shorter than normal inner and outer segments. Determining the function of the Crumbs proteins in photoreceptors may also provide further insight into the early stages of photoreceptor development. To further our understanding of the cellular and molecular mechanisms that underlie photoreceptor morphogenesis we propose three specific aims: (1) Examine the role of Crb2a in regulating photoreceptor and Muller glial morphology. (2) Examine the role of Prkci in regulating Crumbs protein function and photoreceptor and Muller glial morphology. (3) Examine the role of Rhophilin 1 (Rhpn1), a protein that interacts with Moe/Epb41l5, in regulating Crumbs protein function. An additional long-term goal of our studies is to generate tools to test the causal relationship between outer and inner segment size and photoreceptor degeneration because a shortening of inner and outer segments is often observed prior to photoreceptor degeneration. PUBLIC HEALTH RELEVANCE: This proposal seeks to expand our understanding of how vertebrate photoreceptors attain and maintain their unique functional morphology. Photoreceptor degeneration is the cause of most forms of vision loss and yet we understand very little about why or how these cells die. Our research is aimed towards prolonging the survival and function of photoreceptors during disease processes.