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：
8047972
负责人：
ABIGAIL M JENSEN
金额：
$ 37.59万
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/8047972
关键词：
Affect Binding Binding Sites Blindness Cells Chemicals Co-Immunoprecipitations Complex Data Defect Development Disease Dominant-Negative Mutation Drosophila genus EGF gene Embryo Extracellular Domain Eye Genes Genetic Goals 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.

描述（由申请人提供）：光感受器是对光做出反应并将其转化为化学信号的主要细胞，并且是受光感受器变性疾病影响的细胞，包括黄斑变性、色素性视网膜炎（RP）和其他遗传性视网膜变性。尽管许多基因突变已被发现与光感受器变性疾病相关，但我们对这些突变为何导致光感受器死亡仍然知之甚少。该提案旨在扩大我们对脊椎动物光感受器如何获得和维持其独特的功能形态以及光感受器形态与生存之间关系的理解。我们已经证明，含有蛋白质 Mosaic eyes (Moe) 的 FERM 结构域是 Crumbs 蛋白功能的重要调节因子，直接与 Crumbs 蛋白相互作用，并且还表明缺乏 Moe 功能的视杆光感受器具有比正常更大的外部节段。据我所知，这是第一个基因功能丧失的例子，导致外节大于正常，而不是小于正常。人类 CRUMBS 同源物 1 (CRB1) 的突变与两种视力丧失疾病相关，即莱伯氏先天性黑蒙和色素性视网膜炎 12。这些疾病的严重程度和发病早表明 CRB1 功能对于光感受器发育的早期阶段至关重要，并表明了解 CRB1 和相关蛋白在光感受器中的作用可能会让我们深入了解治疗 LCA 和 RP12 的方法。缺乏 Crb1 功能的小鼠的光感受器的内节和外节比正常的短。确定光感受器中 Crumbs 蛋白的功能也可以进一步了解光感受器发育的早期阶段。为了进一步了解光感受器形态发生的细胞和分子机制，我们提出了三个具体目标：（1）检查 Crb2a 在调节光感受器和米勒胶质细胞形态中的作用。 (2)考察Prkci在调节Crumbs蛋白功能以及光感受器和Muller胶质细胞形态方面的作用。 (3) 检查Rhophilin 1 (Rhpn1)（一种与Moe/Epb41l5 相互作用的蛋白质）在调节Crumbs 蛋白质功能中的作用。我们研究的另一个长期目标是生成工具来测试外节和内节大小与光感受器变性之间的因果关系，因为在光感受器变性之前经常观察到内节和外节的缩短。公共健康相关性：该提案旨在扩大我们对脊椎动物光感受器如何获得并保持其独特功能形态的理解。光感受器变性是大多数形式的视力丧失的原因，但我们对这些细胞死亡的原因或方式知之甚少。我们的研究旨在延长疾病过程中光感受器的存活和功能。