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的基因功能丧失突变引起的。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。众所周知，OCRL是一种由体内所有细胞表达的酶，其主要功能是使肌醇环5位的两个双层磷脂PI(4，5)P2和PI(3，4，5)P3去磷酸化，但这种酶的催化活性缺陷导致疾病，特别是肾脏疾病的机制尚不清楚。这个项目的目标是阐明这种机制。强有力的证据表明，OCRL的一个主要功能是避免其底物积聚在内吞途径的膜上。推测导致这些脂类，主要是PI(4，5)P2在细胞内的不适当聚集，导致异位肌动蛋白成核和膜蛋白沿内吞途径的异常运输和分选。这一效应预计将对近端小管细胞产生巨大的影响，因为大量的内吞活动发生在它们富含光化的顶端。在这个方案中，我们计划阐明由OCRL控制的细胞内肌醇磷脂池的生理功能，确定这些池如何调节肌动蛋白核和内体运输，并确定这些事件如何在模型小鼠和细胞系中特异性地影响肾脏近端小管细胞的功能。

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.