Glaucoma Pathogenesis of Oculocerebrorenal syndrome of Lowe

Lowe眼脑肾综合征青光眼发病机制

• 批准号: 8223419
• 负责人: Yang Sun
• 金额: $ 20.47万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223419
• 关键词: Accounting; Affect; Affinity Chromatography; African American; Apical; Binding; Biochemical; Blindness; Brain Diseases; Cell Polarity; Cell Volumes; Cell membrane; Cells; Clinical; Complex; Confocal Microscopy; Defect; Development; Development Plans; Disease; Disease model; Doctor of Philosophy; Dynein ATPase; Early Endosome; Enzymes; Epithelium; Exhibits; Eye; Family; Family member; Fibroblasts; Filtration; Functional disorder; Funding; Genes; Glaucoma; Goals; Human; Hydrogen Chloride; Hydrophthalmos; Immunohistochemistry; Inherited; Inositol; Intervention; Ion Channel; Kidney; Kidney Diseases; Kinesin; Knockout Mice; Knowledge; Laboratories; Lead; Link; Mediating; Membrane Proteins; Mental Retardation; Mentors; Microtubules; Modeling; Molecular; Motor; Mus; Oculocerebrorenal Syndrome; Ophthalmologist; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphatidylinositols; Physiologic Intraocular Pressure; Production; Protein phosphatase; Proteins; Proteomics; Regulation; Research; Risk Factors; Role; Scientist; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; Surface; Tissues; Trabecular meshwork structure; Training; Yin; apical membrane; aqueous; base; career; career development; congenital cataract; disease-causing mutation; inositol-1,4,5-trisphosphate 5-phosphatase; insight; knock-down; lipid mediator; member; mutant; myo-inositol-1 (or 4)-monophosphatase; novel; protein transport; research study; small hairpin RNA; small molecule; symporter; therapeutic development; therapeutic target; tool; trafficking; trans-Golgi Network

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. PUBLIC HEALTH RELEVANCE: Glaucoma is a leading cause of irreversible blindness in the world, yet the mechanisms of glaucoma development remain poorly understood and the treatments are limited. This proposal outlines research to understand the mechanism of an inherited form of congenital glaucoma, in the hopes that this will provide insight and potentially lead to novel treatments for commonly seen forms of glaucoma.

描述（由申请人提供）：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发病机制，使用Lowe眼脑肾综合征作为模型疾病。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醇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。青光眼是世界上不可逆性失明的第二大原因，并且是非裔美国人失明的主要原因。已知眼内压（IOP）升高是一个强风险因素，并且仍然是干预的唯一目标，但对导致IOP升高的机制仍知之甚少。我们已经发现了眼内囊泡运输的重要调节剂的证据，其可以控制IOP。Lowe综合征（OCRL 1）是一种X连锁疾病，其特征是青光眼和先天性白内障，以及脑和肾脏疾病。OCRL 1蛋白是一种肌醇多磷酸5-磷酸酶，控制磷酸肌醇的水平，而磷酸肌醇反过来又在囊泡运输中很重要。我们建议通过研究OCRL 1和驱动蛋白马达蛋白之间的相互作用来研究OCRL 1介导的囊泡转运机制。我们的目的是（1）描述OCRL 1在人和小鼠眼中的分布和表达，（2）确定OCRL 1是否通过与驱动蛋白家族成员结合来介导沿着微管的囊泡运输，以及（3）确定OCRL 1是否是小梁网上皮中顶端膜蛋白运输所必需的。该提案的资助将最终促进发现新的青光眼疗法，可以减少失明的负担。 公共卫生关系：青光眼是世界范围内导致不可逆性失明的主要原因，但青光眼发生的机制仍然知之甚少，治疗方法也有限。该提案概述了了解遗传性先天性青光眼机制的研究，希望这将提供洞察力，并可能导致常见青光眼形式的新治疗方法。