The Role of Nephrocystin-5 in Retinal Degeneration

描述（由申请人提供）：肾痨是一种遗传性囊性肾病。该病有许多肾外表现。肾单位营养不良最常见的相关病理之一是视网膜变性（视网膜色素变性或Leber先天性黑蒙）的发展。这种累及肾脏和视网膜的临床表现被诊断为老年-洛肯综合征。肾单位结核的发生主要归因于几种肾囊蛋白的突变，这些蛋白被认为对细胞中初级纤毛的发育和正常功能很重要。有趣的是，几乎在所有的老年-洛肯综合征患者中都发现了NPHP 5的突变。然而，目前仍然不知道NPHP 5的正常功能以及NPHP 5突变如何导致视网膜变性。本论文的目的是建立视网膜变性的体内和体外模型，研究NPHP 5在视网膜变性发生发展中的作用。第一个目标是在小鼠的视杆细胞中开发NPHP 5的条件性敲除，以了解蛋白质的缺乏如何导致视网膜色素变性样视网膜变性的发展。第二个目的是研究NPHP 5在体外细胞培养系统中控制细胞极性的预测作用中的作用。! ! 公共卫生相关性：老年洛肯综合征是一种影响肾脏和视网膜的衰弱性疾病。影响视网膜的疾病是称为视网膜色素变性（RP）的眼睛的光感受器的进行性变性。目前，没有治愈RP的方法。NPHP 5基因的突变会导致Senior-Loken综合征。该项目提案旨在了解NPHP 5突变如何导致视网膜变性。这与社会非常相关，因为它将确定导致疾病的具体机制，并可能发现RP药物治疗的新靶点。

DESCRIPTION (provided by applicant): Nephronophthisis is a genetic cystic kidney disease. There are numerous extrarenal manifestations of the disease. One of the most common associated pathologies of nephronophthisis is the development of retinal degeneration (Retinitis Pigmentosa or Leber Congenital Amaurosis). This clinical finding involving the kidneys and the retina is given the diagnosis of Senior-Loken syndrome. Development of nephronophthisis has been attributed primarily to mutations in several nephrocystin proteins, which are thought to be important in the development and normal function of the primary cilium in cells. Interestingly, mutations in NPHP5 have been found in virtually all Senior-Loken syndrome patients. However, it is still currently not known what the normal function of NPHP5 and how NPHP5 mutations contribute to retinal degeneration. The goal of this thesis project is to establish both in vivo an in vitro models to study the normal role of NPHP5 as it relates to development of retinal degeneration. The first aim is to develop a conditional knock out of NPHP5 in rod photoreceptor cells of mice to understand how absence of the protein may lead to development of retinitis pigmentosa-like retinal degeneration. The second aim is to investigate the role of NPHP5 in its predicted role of controlling cellular polarity in an in vitro cell culture system. ! ! PUBLIC HEALTH RELEVANCE: Senior-Loken syndrome is a debilitating disease that affects the kidneys and the retina. Disease affecting the retina is a progressive degeneration of photoreceptors of the eye called Retinitis Pigmentosa (RP). Currently, there is no cure for RP. Mutations in the gene, NPHP5, cause Senior-Loken syndrome. This project proposal aims to understand how mutations in NPHP5 lead to retinal degeneration. This is very relevant to society as it will determine specific mechanisms leading to disease and potentially discover new targets for pharmacological treatment of RP.