Glaucoma Pathogenesis of Oculocerebrorenal syndrome of Lowe

应聘者描述(申请人提供)：应聘者是一名医学博士/博士学位的临床眼科医生，职业目标是研究青光眼的发病机制，以LOWE的眼脑肾综合征为模型疾病。这项职业发展计划将由杰弗里·特拉弗斯博士和张中银博士共同指导，他们的实验室专注于脂质介体和蛋白磷酸酶的分子信号通路。候选人的长期目标是了解肌醇磷脂信号在眼睛中的作用，特别是关于水的产生和过滤，以确定治疗开发的新靶点。青光眼是世界上导致不可逆转失明的第二大原因，也是导致非裔美国人失明的首要原因。高眼压(IOP)已被认为是一个强烈的危险因素，并仍然是干预的唯一目标，但导致高眼压的机制仍然知之甚少。我们已经发现了眼内囊泡运输的一个重要调节器的证据，该调节器可能控制眼压。洛威综合征(OCRL1)是一种X连锁疾病，以青光眼、先天性白内障以及脑和肾脏疾病为特征。OCRL1蛋白是一种肌醇多磷酸5-磷酸酶，它控制着磷脂酰肌醇的水平，而磷脂酰肌醇在囊泡运输中起着重要的作用。我们建议通过检测OCRL1和运动蛋白马达蛋白之间的相互作用来研究OCRL1介导的囊泡转运的机制。我们的目标是(1)确定OCRL1在人和小鼠眼睛中的分布和表达；(2)确定OCRL1是否通过与Kinesin家族成员结合来介导囊泡沿微管的运输；(3)确定OCRL1是否是小梁网络上皮细胞顶膜蛋白运输所必需的。这项提案的资金最终将有助于发现可以减轻失明负担的青光眼新疗法。

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.