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构成脊椎动物视杆细胞和视锥细胞外节（OS）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。虽然在描述光转导级联反应方面取得了很大进展，但在分子水平上对感光细胞外节（OS）的结构组织仍然知之甚少。我们建议推进OS架构的知识，为理解支架缺陷如何损害视杆细胞和视锥细胞的活力，导致视网膜疾病提供基础。我们以前的研究已经阐明了结构/功能关系的外周蛋白/rds（P/rds），光受体特异性四跨膜蛋白，视杆细胞和视锥细胞的完整性起着至关重要的作用，并产生一个独特的广泛的进行性视网膜疾病时，有缺陷的。我们将评估的假设，P/rds是多功能的，它的自组装，蛋白质支架和膜结合活性，代表其支持OS结构和感光细胞的活力，并参与不同的疾病表型的基石。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OS支架相互作用。特异性目的3将阐明P/rds胞质活性的意义和调节。总之，这些研究解决了目前感光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。他们推进我们的光感受器结构的分子解剖，并将提供一个新的系统，在脊椎动物光感受器的蛋白质-蛋白质相互作用的发现和体内分析。 视网膜光感受器为视觉提供细胞基础。这些脆弱的细胞使用高度组织化的“外部部分”来探测入射的光子。由外伤或遗传性疾病引起的外节结构紊乱可损害感光细胞功能和活力，从而引起广泛的视网膜疾病。该项目将提供对健康和疾病中的光感受器外节结构的更好理解。

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.