Molecular scaffolding for photoreceptor outer segment structure and renewal.

描述（由申请人提供）：本提案的长期目标是定义脊椎动物杆状和锥状光感受器外段（OSs）动态结构基础的分子支架。视网膜光感受器为现代生物学提供了重要的范式，包括g蛋白介导的信号转导和神经退行性疾病的机制。尽管在描述光传导级联方面已经取得了很好的进展，但在分子水平上对光感受器外段（OS）的结构组织仍然知之甚少。我们建议提高OS结构的知识，为理解支架缺陷如何损害视杆细胞和视锥细胞的活力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，P/rds是一种光感受器特异性的四联蛋白，对视杆细胞和视锥细胞的完整性起重要作用，并且当缺陷时产生独特的广泛的进行性视网膜疾病。我们将评估P/rds是多功能的假设，其自组装、蛋白支架和膜结合活性是其支持OS结构和光感受器活力的关键，并参与多种疾病表型。特异性目的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将确定和验证新的操作系统脚手架交互。特异性目的3将阐明P/rds细胞质活性的意义和调控。总之，这些研究解决了当前对光感受器细胞生物学和RDS缺陷致病性的分子基础的理解的关键空白。他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。

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.