Glaucoma Pathogenesis of Oculocerebrorenal syndrome of Lowe

描述（由申请人提供）：该候选人是一名医学博士/博士培训的临床眼科医生，其职业目标是研究青光眼的发病机制，以Lowe眼脑肾综合征为模型疾病。职业发展计划将由Jeffrey Travers博士和Zhong-yin Zhang博士共同指导，他们的实验室专注于脂质介质和蛋白磷酸酶的分子信号通路。候选人的长期目标是了解磷酸肌苷信号在眼睛中的作用，特别是关于水的产生和过滤，以便为治疗开发确定新的靶点。青光眼是世界上导致不可逆失明的第二大原因，也是导致非裔美国人失明的主要原因。众所周知，眼压升高是一个强烈的危险因素，也是干预的唯一目标，但引起眼压升高的机制仍然知之甚少。我们已经发现了一种可能控制IOP的重要的眼内囊泡运输调节剂的证据。Lowe综合征（OCRL1）是一种以青光眼、先天性白内障以及脑和肾脏疾病为特征的x连锁疾病。ocl1蛋白是一种肌醇多磷酸5-磷酸酶，它控制磷酸肌苷的水平，而磷酸肌苷在水泡运输中又很重要。我们建议通过检测OCRL1与运动蛋白之间的相互作用来研究OCRL1介导的囊泡运输机制。我们的目的是：(1)表征OCRL1在人和小鼠眼睛中的分布和表达，(2)确定OCRL1是否通过与激酶家族成员结合介导微管的囊泡运输，以及(3)确定OCRL1是否需要在小梁网上皮中运输顶膜蛋白。这项提案的资金将最终促进新的青光眼疗法的发现，从而减轻失明的负担。

DESCRIPTION (provided by applicant): The candidate is an MD/PhD trained clinical ophthalmologist with the career goal of investigating the mechanisms of glaucoma pathogenesis, using oculocerebrorenal syndrome of Lowe as a model disease. The career development plan will be jointly mentored by Dr. Jeffrey Travers and Dr. Zhong-yin Zhang, whose laboratories focus on the molecular signaling pathways of lipid mediators and protein phosphatases. The candidate's long-term aim is to understand the roles of phosphoinositide signaling in the eye, specifically regarding aqueous production and filtration, in order to identif novel targets for therapeutic development. Glaucoma is the second leading cause of irreversible blindness in the world and is the leading cause of blindness in African Americans. Elevated intraocular pressure (IOP) has been known to be a strong risk factor and remains the only target for intervention, but the mechanisms causing elevated IOP remain poorly understood. We have found evidence of an important regulator of vesicular trafficking in the eye that may control IOP. Lowe syndrome (OCRL1) is an X-linked disorder characterized by glaucoma and congenital cataracts, as well as brain and kidney diseases. The OCRL1 protein is an inositol polyphosphate 5-phosphatase that controls the levels of phosphoinositides, which in turn are important in vesicular trafficking. We propose to study the mechanism of OCRL1-mediated vesicular transport by examining the interaction between OCRL1 and kinesin motor proteins. Our aims are to (1) characterize the distribution and expression of OCRL1 in human and mouse eyes, (2) determine whether OCRL1 mediates vesicular trafficking along microtubules by binding to kinesin family members, and (3) determine whether OCRL1 is required for the trafficking of apical membrane proteins in trabecular meshwork epithelium. The funding of this proposal will ultimately facilitate the discovery of new glaucoma therapies that can reduce the burden of blindness.