Cellular and Molecular Mechanisms Regulating Photoreceptor Morphology

调节光感受器形态的细胞和分子机制

• 批准号: 7637604
• 负责人: ABIGAIL M JENSEN
• 金额: $ 36.91万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7637604
• 关键词: Affect; Antisense Oligonucleotides; Apical; Binding; Binding Sites; Biological Assay; Blindness; C-terminal; Cell Polarity; Cells; Chemicals; Co-Immunoprecipitations; Complex; Data; Defect; Development; Disease; Dominant-Negative Mutation; Drosophila genus; EGF gene; Embryo; Erythrocytes; Extracellular Domain; Eye; Genes; Genetic; Glutathione S-Transferase; Goals; Homologous Gene; Human; In Vitro; Inherited; Knowledge; Leber' s amaurosis; Light; Localized; Macular degeneration; Mass Spectrum Analysis; Messenger RNA; Molecular; Morphogenesis; Morphology; Mus; Mutation; Orthologous Gene; PDZ protein; Pathway interactions; Phosphotransferases; Photoreceptors; Play; Proteins; Retinal Degeneration; Retinitis Pigmentosa; Role; Severities; Signal Transduction; Staging; Testing; Transgenic Organisms; Transmembrane Domain; Vertebrate Photoreceptors; Yeasts; Zebrafish; apical membrane; band 4.1 protein; early onset; gene function; insight; interest; knock-down; loss of function; mutant; photoreceptor degeneration; protein function; protein kinase C iota; research study; retinal rods; size; tool; yeast two hybrid system

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. 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) Characterize the role of specific domains of Crb2a in regulating rod photoreceptor morphogenesis. (2) Examine the role of Prkci/aPKC?? in regulating Crumbs function and rod photoreceptor morphology. (3) Identify additional proteins that interact with Moe/Epb4.1l5. A 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. This raises the interesting question as to whether this phenomenon is causal or whether compromised or sick photoreceptors are unable to maintain their inner and outer segments.

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。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具体目标：(1)表征特定的作用 Crb2a调控杆状感光细胞形态发生的结构域。(二)检视 Prkci/aPKC？？在调节Crumbs功能和杆光感受器形态方面。(3)确定其他 与MoE/Epb4.1l5相互作用的蛋白质。我们研究的一个长期目标是生成测试工具 内外节段大小与感光细胞退行性变的因果关系 因为内、外节段的缩短通常先于光感受器 退化。这提出了一个有趣的问题，即这种现象是因果的还是 无论是受损的还是生病的，光感受器都无法维持其内部和外部部分。