Cellular and Molecular Mechanisms Regulating Photoreceptor Morphology

光感受器是对光线做出反应并将其转化为化学物质的主要细胞 是感光细胞变性疾病（包括黄斑变性）中受影响的细胞。 视网膜变性、色素性视网膜炎（RP）和其它遗传性视网膜变性。虽然 已经鉴定出许多基因的突变与光感受器退化有关 虽然我们对这些突变导致光感受器死亡的原因仍然知之甚少。这 一项提案旨在扩大我们对脊椎动物光感受器如何获得和维持 它们独特的功能形态以及感光细胞形态与 生存 我们已经表明，含有FERM结构域的蛋白质镶嵌眼（莫伊）是一个重要的 Crumbs蛋白功能的调节因子，直接与Crumbs蛋白相互作用，并且还表明， 缺乏莫伊功能的视杆细胞感光器具有比正常细胞更大的外节。到我 这是第一个基因功能丧失的例子，导致比正常情况下更大的 而不是更小的一个。人类CRUMBS同源物1（CRB 1）的突变 与两种视力丧失疾病有关，即先天性黑蒙和色素性视网膜炎 12.这些疾病的严重性和早期发作表明CRB 1功能对于早期免疫至关重要。 感光细胞发育的各个阶段，并建议了解CRB 1及相关基因的作用 光感受器中的蛋白质可以让我们了解治疗LCA和RP 12的方法。光感受器 缺乏Crb 1功能的小鼠具有比正常的内节和外节短的长度。确定 Crumbs蛋白在光感受器中的功能也可能提供对早期 感光细胞发育的阶段。 为了加深我们对细胞和分子机制的理解， 我们提出三个具体目标：（1）研究Crb 2a在光感受器形态发生中的作用， 调节光感受器和M？ller神经胶质形态。(2)研究Prkci在调节 Crumbs蛋白功能和光感受器及M？ller胶质细胞形态。(3)审查的作用 Rhophilin 1（Rhpn 1）是一种与莫伊/Epb 41 l5相互作用的蛋白，在调节Crumbs蛋白中起作用 功能我们研究的另一个长期目标是生成测试因果关系的工具。 外节和内节大小与感光细胞变性之间的关系， 内节和外节的缩短通常在光感受器退化之前观察到。

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 M¿ller glial morphology. (2) Examine the role of Prkci in regulating Crumbs protein function and photoreceptor and M¿ller 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.