Molecular scaffolding for photoreceptor outer segment structure and renewal.

描述(由申请人提供)：这项提案的长期目标是定义脊椎动物视杆和视锥感光细胞外节(OSS)动态结构的分子支架。视网膜光感受器为现代生物学提供了重要的范例，包括G蛋白介导的信号转导和神经退行性疾病的潜在机制。尽管在描述光转导级联方面已经取得了很大的进展，但光感受器外段(OS)的结构组织在分子水平上仍然知之甚少。我们建议推进OS架构的知识，为了解支架缺陷如何损害视杆细胞和视锥细胞的活性而导致视网膜疾病提供基础。我们之前的研究已经阐明了外周蛋白/rds(P/rds)的结构/功能关系，外周蛋白/rds是一种光感受器特异性的四环素，它对视杆细胞和视锥细胞的完整性起着至关重要的作用，当缺陷时会产生一系列独特的进行性视网膜疾病。我们将评估P/rds是多功能的假设，以及它的自组装、蛋白质支架和膜结合活性是其支持OS结构和光感受器活性的关键，并参与不同的疾病表型。具体目标1将阐明已知的P/RDS相互作用、OS盘形态发生和视网膜疾病之间的关系。具体目标2将识别和验证新的操作系统脚手架交互。具体目标3将阐明P/rds细胞质活性的意义和调控。总而言之，这些研究解决了目前对光感受器细胞生物学理解的关键空白，以及RDS缺陷引起的致病性的分子基础。它们推进了我们对光感受器结构的分子解剖，并将为脊椎动物光感受器中蛋白质-蛋白质相互作用的发现和体内分析提供一个新的系统。 视网膜光感受器为视力提供了细胞基础。这些脆弱的细胞使用高度组织化的“外层部分”来探测入射的光子。外伤或遗传性疾病引起的外节结构紊乱可损害光感受器的功能和生存能力，从而导致多种视网膜疾病。该项目将为更好地了解光感受器外节结构在健康和疾病中的作用提供依据。

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to define the molecular scaffolding that underlies the dynamic architecture of vertebrate rod and cone photoreceptor outer segments (OSs). Retinal photoreceptors provide important paradigms for modern biology, including mechanisms underlying G-protein mediated signal transduction and neurodegenerative diseases. Although excellent progress has been made in describing the phototransduction cascade, the structural organization of the photoreceptor outer segment (OS) remains poorly understood at the molecular level. We propose to advance knowledge of OS architecture to provide a basis for understanding how scaffolding defects impair rod and cone cell viability to cause retinal disease. Our previous studies have elucidated structure/function relationships for peripherin/rds (P/rds), a photoreceptor-specific tetraspanin that plays an essential role for rod and cone cell integrity, and generates a uniquely broad range of progressive retinal diseases when defective. We will evaluate the hypothesis that P/rds is multifunctional, and that its self-assembly, protein scaffolding, and membrane binding activities, represent keystones for its support of OS structure and photoreceptor viability, and involvement in diverse disease phenotypes. Specific Aim 1 will elucidate relationships between known P/rds interactions, OS disk morphogenesis, and retinal disease. Specific Aim 2 will identify and validate novel OS scaffolding interactions. Specific Aim 3 will elucidate the significance and regulation of P/rds cytoplasmic activities. In sum, these studies address critical gaps in current understanding of photoreceptor cell biology, and the molecular basis of pathogenicity caused by RDS defects. They advance our molecular dissection of photoreceptor architecture, and will provide a new system for the discovery and in vivo analysis of protein-protein interactions in vertebrate photoreceptors. Retinal photoreceptors provide the cellular basis for sight. These fragile cells use a highly organized "outer segment" to detect incoming photons. Disorganization of outer segment architecture by trauma or inherited disease can impair photoreceptor function and viability to cause a wide range of retinal diseases. This project will provide a better understanding of photoreceptor outer segment structure in health and disease.