OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

OCRL 与 Lowe 综合征和 Dent 病的发病机制

• 批准号: 8117214
• 负责人: Pietro De Camilli
• 金额: $ 28.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117214
• 关键词: Address; Affect; Apical; Biochemical; Cell Line; Cell membrane; Cell physiology; Cells; Clathrin; Clathrin Adaptors; Clinical; Defect; Disease; Early Endosome; Endocytosis; Endosomes; Enzymes; Fanconi Syndrome; Foundations; Functional disorder; Genes; Goals; Golgi Apparatus; Health; Homologous Gene; Inositol; Ion Channel; Kidney; Kidney Diseases; Knowledge; Laboratories; Link; Lipids; Medical; Membrane Proteins; Mental Retardation; Metabolism; Modeling; Molecular; Mus; Mutation; Oculocerebrorenal Syndrome; Organ; Pathogenesis; Pathology; Pathway interactions; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Play; Positioning Attribute; Property; Protein Dephosphorylation; Proteins; Proximal Kidney Tubules; Recycling; Renal function; Reporting; Role; Signal Transduction; Site; Sorting - Cell Movement; System; TFAP2A gene; Therapeutic; Work; congenital cataract; human disease; inositol-1,4,5-trisphosphate 5-phosphatase; kidney cell; novel; prevent; receptor; therapy design; therapy development; trafficking; treatment strategy

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.

描述（由申请人提供）：本提案的长期目标是制定治疗两种人类疾病的治疗策略，即罗氏眼-脑-肾综合征（罗氏综合征）和登特病，这两种疾病是由编码肌醇5-磷酸酶ocl的基因突变引起的。洛氏综合征是一种严重的x连锁疾病，其特征是肾近端小管重吸收缺陷（肾范可尼综合征）、智力低下和先天性白内障。Dent病是另一种x连锁疾病，其临床表现仅限于与Lowe综合征相似的肾脏缺陷。虽然已知ocl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，因为肾脏是受ocl基因突变持续影响的器官。最近在细胞水平上的研究表明，ocl的主要作用位点是早期内吞途径，其中几种主要的ocl相互作用物集中，如网格蛋白、网格蛋白接头AP-2、Rab5和内吞接头APPL1。一个主要的工作假设是，由ocl功能受损引起的PI(4,5)P2和可能的PI(3,4,5)P3水平异常导致肾近端小管细胞中顶质膜蛋白的运输和分选异常。在本研究中，我们计划进一步表征ocl及其同系物INPP5B的分子特性和相互作用，阐明ocl在肾近端小管细胞和模型细胞系中的内噬运输和内体动力学中的作用，确定ocl /INPP5B突变对小鼠肾功能的影响，并鉴定其功能增强或抑制ocl缺失导致的缺陷的蛋白质。这些修饰基因的鉴定可能为理解不同的ocl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和病理中的关键作用，这些研究的结果将进一步与肾脏和其他器官的各种疾病的阐明和治疗相关。公共卫生相关性：罗氏脑肾综合征（罗氏综合征）是一种以肾功能不全、智力迟钝和先天性白内障为特征的严重疾病，由编码脂质代谢酶ocl的基因突变引起。ocl突变也可引起Dent病，其临床表现仅限于与Lowe综合征相似的肾脏缺陷。本提案的目标是了解ocl功能的破坏是如何导致肾脏疾病的，希望这些信息可能有助于制定针对这些疾病的治疗策略。