Investigation of the molecular basis of rod and cone photoreceptor structure

 描述（由申请人提供）：脊椎动物视力和人类视觉健康取决于视杆细胞和视锥细胞外节（OS）的膜结构。各种各样的视力障碍性疾病与OS结构的缺陷有关;然而，无论是潜在的疾病病因，还是受体细胞的基本生物学都没有很好的理解。特别是，负责产生和稳定的成熟杆和锥OS磁盘的结构的分子机制尚不清楚。这项研究的长期目标是足够详细地定义OS架构和更新，以解释缺陷如何产生视网膜疾病并设计有效的治疗策略。目前的目标是确定外周蛋白-2/rds（P/rds）如何作为OS膜的组织者发挥作用。这种完整的膜四跨膜蛋白以基本的、尽管机制上不确定的方式起作用，以支持视杆细胞和视锥细胞的OS结构，并且P/rds中的遗传突变引起广泛的进行性疾病，包括色素性视网膜炎和黄斑变性。本研究的第一个目的是确定已知的蛋白质结构/调节决定因素的重要性P/rds诱导高度弯曲的膜。第二个目标将测试的假设，P/rds C-末端通常是膜相关的诱导型两亲性螺旋，可以起到栓在一起的OS磁盘边缘分区。第三个目标将检验P/rds C-末端结构域中的致病性突变可以优先影响视锥光感受器的假设。成功完成所提出的工作将提高P/rds蛋白结构-功能的知识，阐明P/rds如何产生高曲率膜以形成和稳定OS盘，并将为理解P/rds中的致病突变如何优先影响视锥（与视杆）光感受器提供机制基础。这项工作还可以通过提出新的策略来管理由OS结构中的原发性病理引起的进行性视网膜变性，从而产生积极的影响。

 DESCRIPTION (provided by applicant): Vertebrate sight and human visual health depend upon the membranous architecture of rod and cone photoreceptor outer segments (OSs). A broad variety of sight-robbing diseases is associated with defects in OS architecture; however, neither the underlying disease etiologies, nor the fundamental biology of the receptor cells is well understood. In particular, the molecular mechanisms responsible for generating and stabilizing the structure of mature rod and cone OS disks are not yet known. The long-term goal of this research is to define OS architecture and renewal in sufficient detail to explain how defects generate retinal disease and design effective therapeutic strategies. The current goal is to determine how peripherin-2/rds (P/rds) functions as an organizer for OS membranes. This integral membrane tetraspanin acts in an essential, though mechanistically uncertain fashion to support OS architecture for both rods and cones, and inherited mutations in P/rds cause a broad range of progressive diseases, including retinitis pigmentosa and macular degenerations. The first Aim of this study will determine the importance of known protein structural/regulatory determinants for P/rds induction of highly curved membranes. The second Aim will test the hypothesis that the P/rds C-terminus is normally membrane associated via partitioning of an inducible amphipathic helix that can function to tether OS disk rims together. The third Aim will test the hypothesis that pathogenic mutations in the P/rds C-terminal domain can preferentially impact cone photoreceptors. Successful completion of the work proposed would improve knowledge of P/rds protein structure-function, clarify how P/rds can generate high curvature membranes to form and stabilize OS disks, and would provide a mechanistic basis for understanding how pathogenic mutations in P/rds preferentially affect cone (vs. rod) photoreceptors. The work could also make a positive impact by suggesting new strategies for managing progressive retinal degenerations that result from primary pathologies in OS structure.