Cellular and Molecular Mechanisms Regulating Photoreceptor Morphology

光感受器是对光作出反应并将其转化为化学物质的初级细胞 信号和细胞是否在包括黄斑在内的感光细胞变性疾病中受到影响 视网膜变性、视网膜色素变性(RP)和其他遗传性视网膜变性。虽然 许多基因的突变与光感受器退行性变有关 对于疾病，我们仍然知之甚少，为什么这些突变会导致光感受器死亡。这 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的理解 它们独特的功能形态及其与光感受器形态的关系 生死存亡。 我们已经证明了含有蛋白嵌合眼的FERM结构域(MOE)是一个重要的 Crumbs蛋白功能的调节者，直接与Crumbs蛋白相互作用，也表明 缺乏MOE功能的杆状感光器的外节比正常的要大。致我的 这是第一个基因功能丧失导致的比正常更大的例子 外部段，而不是较小的段。人类面包屑同系物1(CRB1)的突变 与两种视力丧失疾病有关，Leber先天性黑色素和视网膜色素变性 12.这些疾病的严重性和早期发病表明CRB1功能对早期 光感受器发育的各个阶段，并提示理解CRB1及其相关的作用 光感受器中的蛋白质可能会让我们深入了解治疗LCA和Rp12的方法。中的光感受器 缺乏Crb1功能的小鼠的内节和外节比正常的小鼠短。确定 Crumbs蛋白在光感受器中的功能也可能为进一步了解早期的 光感受器发育的各个阶段。 为了加深我们对细胞和分子机制的理解 光感受器的形态发生我们提出了三个特定的目标：(1)研究Crb2a在光感受器形态发生中的作用 调节光感受器和M？ler神经胶质的形态。(2)研究PRKCI在调节中的作用 面包屑蛋白功能、光感受器和M？ler神经胶质细胞形态。(三)检视 亲红细胞素1(Rhpn1)是一种与MoE/Epb4115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 外节和内节大小与光感受器退变的关系 在感光细胞变性之前，常可观察到内、外节段缩短。

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.