OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

OCRL 与 Lowe 综合征和 Dent 病的发病机制

基本信息

批准号：
8577200
负责人：
Pietro De Camilli
金额：
$ 28.97万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8577200
关键词：
Aarskog syndrome Actins Affect Apical Back Cell Line Cell membrane Cell physiology Cells Cilia Clinical Cytokinesis Defect Disease Endocytosis Enzymes Event Family Fanconi Syndrome Functional disorder Genes Goals Homeostasis Homologous Gene Impairment Inositol Intracellular Accumulation of Lipids Intracellular Membranes Ion Exchange Kidney Kidney Diseases Knowledge Light Link Medical Membrane Membrane Protein Traffic Membrane Proteins Mental Retardation Modeling Molecular Mouse Cell Line Mus Mutation Oculocerebrorenal Syndrome Pathogenesis Pathway interactions Phenotype Phosphatidylinositols Phospholipids Phosphoric Monoester Hydrolases Physiological Polyphosphates Positioning Attribute Protein Family Proteins Proximal Kidney Tubules Recycling Regulation Role Sorting - Cell Movement Surface Testing Therapeutic Work arm congenital cataract enzyme activity feeding glomerular filtration human disease inositol-1,4,5-trisphosphate 5-phosphatase loss of function loss of function mutation member neuronal cell body protein transport public health relevance therapy design trafficking treatment strategy

项目摘要

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 loss-of-function 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, an enzyme expressed by all cells of the body, is to dephosphorylate two bilayer phospholipids, PI(4,5)P2 and PI(3,4,5)P3 (members of the phosphoinositide family) at the 5 position of their inositol ring, the mechanisms through which a defect in the catalytic activity of this enzyme cause disease, and specifically kidney disease, remain unclear. The objective of this project is to elucidate such mechanisms. Strong evidence indicates that a main function of OCRL is to avoid accumulation of its substrates on membranes of the endocytic pathway. It is hypothesized that the resulting inappropriate intracellular accumulation of these lipids, primarily PI(4,5)P2, leads to ectopic actn nucleation and abnormal traffic and sorting of membrane proteins along the endocytic pathway. This effect is expected to have a dramatic impact on proximal tubule cells due the massive endocytic activity occurring at their actinrich apical pole. In this proposal we plan to elucidate he physiological function of the intracellular phosphoinositide pools controlled by OCRL, to determine how such pools regulate actin nucleation and endosomal traffic, and to establish how these events specifically affect the function of kidney proximal tubule cells in model mouse and cell lines.

描述（由申请人提供）：该提案的长期目标是制定治疗两种人类疾病的治疗策略，即Lowe（Lowe综合征）的Oculo-Cerebro-肾脏综合征和DENT疾病，这是由于编码Inositol 5-磷酸酶Ocrl的基因丧失功能突变而导致的。 Lowe综合征是一种严重的X连锁障碍，其特征是肾脏近端小管（肾脏范科尼综合征），智力低下和先天性白内障中的重吸收缺陷。凹陷疾病是另一种X连锁疾病，其中临床表现仅限于与Lowe综合征相似的肾脏缺陷。 While it is known that the main function of OCRL, an enzyme expressed by all cells of the body, is to dephosphorylate two bilayer phospholipids, PI(4,5)P2 and PI(3,4,5)P3 (members of the phosphoinositide family) at the 5 position of their inositol ring, the mechanisms through which a defect in the catalytic activity of this enzyme cause disease, and特别是肾脏疾病，尚不清楚。该项目的目的是阐明这种机制。有力的证据表明，OCRL的主要功能是避免其底物在内吞途径的膜上积聚。假设这些脂质的不适当细胞内积累，主要是PI（4,5）P2，导致异位ACTN核定成核和异常交通以及沿内吞细胞途径的膜蛋白的分类。由于其actinrich顶端的大量内吞作用，预计该作用对近端小管细胞产生巨大影响。在此提案中，我们计划阐明由OCRL控制的细胞内磷酸肌醇池的生理功能，以确定此类池如何调节肌动蛋白成核和内体流量，并如何特异性地确定这些事件如何特异性地影响模型和细胞系中肾脏近端小管细胞的功能。