OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

描述(由申请人提供)：这项提议的长期目标是开发治疗两种人类疾病的治疗策略，洛威眼脑肾综合征(Lowe综合征)和Dent病，这两种疾病是由编码肌醇5-磷酸酶OCRL的基因突变引起的。Lowe综合征是一种严重的X连锁疾病，以肾脏近端小管的重吸收缺陷(肾Fanconi综合征)、智力低下和先天性白内障为特征。齿状神经病是另一种X连锁疾病，其临床表现仅限于与洛威综合征相似的肾脏缺陷。虽然已知OCRL的主要功能是使肌醇环5位的PI(4，5)P2和PI(3，4，5)P3去磷酸化，但该蛋白的缺陷导致疾病的机制尚不清楚。该项目的目的是阐明肾脏中的这些机制，因为肾脏是持续受到OCRL基因突变影响的器官。最近在细胞水平的研究表明，OCRL的主要作用部位是早期的内吞途径，其中集中了几个主要的OCRL相互作用因子，如网状蛋白、网状蛋白适配器AP-2、Rab5和内吞适配器APPL1。一个主要的工作假设是，由于OCRL功能受损，PI(4，5)P2，可能还有PI(3，4，5)P3的异常水平导致了肾近端小管细胞顶端质膜蛋白的异常运输和分类。在这项建议中，我们计划进一步研究OCRL及其同系物INPP5B的分子特性和相互作用，阐明OCRL在肾脏近端小管细胞和模型细胞系内皮细胞运输和内小体动力学中的作用，确定OCRL/INPP5B突变对小鼠肾功能的影响，并确定其功能增强或抑制因缺乏OCRL而导致缺陷的蛋白质。这些修饰基因的鉴定可能会为了解不同的OCRL突变对Lowe综合征和Dent病的影响以及开发这些疾病的治疗方法提供相关线索。鉴于PI代谢和内体系统在细胞生理学和病理学中的关键作用，这些研究的结果将另外与肾脏和其他器官的各种疾病的阐明和治疗相关。与公共卫生相关：洛威眼脑肾综合征(LOWE综合征)是一种严重的疾病，其特征是肾功能障碍、智力低下和先天性白内障，其原因是编码一种名为OCRL的脂质代谢酶的基因突变。OCRL的突变也可导致Dent病，其临床表现仅限于肾脏缺陷，与Lowe综合征相似。这项建议的目标是了解OCRL功能障碍是如何导致肾脏疾病的，希望这些信息可能有助于制定这些疾病的治疗策略。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to develop therapeutic strategies for the treatment of two human diseases, Oculo-Cerebro-Renal syndrome of Lowe (Lowe syndrome) and Dent disease, which result from mutations in the gene encoding the inositol 5-phosphatase OCRL. Lowe syndrome is a severe X-linked disorder characterized by reabsorption defects in the kidney proximal tubule (renal Fanconi syndrome), mental retardation and congenital cataracts. Dent disease is another X-linked disorder in which the clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. While it is known that the main function of OCRL is to dephosphorylate PI(4,5)P2 and PI(3,4,5)P3 at the 5 position of the inositol ring, the mechanisms through which a defect in this protein causes disease is unclear. The objective of this project is to elucidate these mechanisms in the kidney, as it is the organ consistently affected by mutations in the OCRL gene. Recent studies at the cellular level have suggested that the main site of action of OCRL is the early endocytic pathway, where several major OCRL interactors are concentrated, such as clathrin, the clathrin adaptor AP-2, Rab5 and the endocytic adaptor APPL1. A main working hypothesis is that abnormal levels of PI(4,5)P2, and possibly PI(3,4,5)P3, resulting from impaired OCRL function result in abnormal traffic and sorting of apical plasma membrane proteins in kidney proximal tubule cells. In this proposal we plan to further characterize the molecular properties and interactions of OCRL and of its homologue INPP5B, to elucidate the role of OCRL in endocytic traffic and endosomes dynamics in kidney proximal tubule cells and in model cell lines, to determine the impact of mutations in OCRL/INPP5B on kidney function in mice and to identify proteins whose function enhances or suppresses defects resulting from lack of OCRL. The identification of such modifier genes may provide clues relevant to understanding the impact of different OCRL mutations in Lowe syndrome and Dent disease and toward developing therapies for these conditions. Given the key role of PI metabolism and of the endosomal system in cell physiology and pathology, the results of these studies will be additionally relevant to the elucidation and treatment of a variety of diseases of the kidney as well as other organs. PUBLIC HEALTH RELEVANCE: OculoCerebroRenal Syndrome of Lowe (Lowe Syndrome) is a severe disorder characterized by kidney dysfunction, mental retardation and congenital cataracts, which results from mutations in the gene encoding a lipid metabolizing enzyme called OCRL. Mutations in OCRL can also cause Dent disease, whose clinical manifestations are limited to kidney defects that are similar to those observed in Lowe syndrome. The goal of this proposal is to understand how disruption of OCRL function leads to kidney disease with the hope that this information may help to develop therapeutic strategies for these conditions.