OCRL and the pathogenesis of Lowe Syndrome and Dent Disease

描述（由申请人提供）：本提案的长期目标是开发用于治疗两种人类疾病的治疗策略，即Lowe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的基因中的功能缺失突变引起的。Lowe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综合征相似的肾缺陷。虽然已知OCRL（一种由身体的所有细胞表达的酶）的主要功能是使两种双层磷脂PI（4，5）P2和PI（3，4，5）P3（磷酸肌醇家族的成员）在其肌醇环的5位脱磷酸化，但该酶的催化活性缺陷引起疾病（特别是肾病）的机制仍不清楚。本项目的目标是阐明这种机制。强有力的证据表明，OCRL的主要功能是避免其底物在内吞途径的膜上积累。据推测，这些脂质（主要是PI（4，5）P2）的不适当的细胞内积累导致异位肌动蛋白成核和异常运输以及膜蛋白沿着内吞途径的分选。这种效应预计会对近曲小管细胞产生巨大影响，因为在其富含放线菌素的顶端发生了大量的内吞活动。在这个提议中，我们计划阐明由OCRL控制的细胞内磷酸肌醇池的生理功能，以确定这些池如何调节肌动蛋白成核和内体运输，并确定这些事件如何具体影响模型小鼠和细胞系中肾近曲小管细胞的功能。

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.