Exploring the relationship of water flow across the RPE and mutant-MYO7A/Usher 1B

探索穿过 RPE 的水流与突变体 MYO7A/Usher 1B 的关系

基本信息

批准号：
9886098
负责人：
DAVID S WILLIAMS
金额：
$ 23.4万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886098
关键词：
Actins Active Biological Transport Affect Apical Blindness Blood flow Carbonic Anhydrase Inhibitors Carrier Proteins Cell Culture Techniques Cell surface Complex Cystoid Macular Edema Defect Disease ES Cell Line Edema Epithelial Attachment Frequencies Genes Genetic Human Impairment Incidence Ion Transport Ions Link Liquid substance MYO7A gene Melanosomes Mus Mutation Myosin ATPase Patients Phagosomes Pharmaceutical Preparations Pharmacological Treatment Pharmacology Proteins RPE65 protein Regulation Reporting Research Resistance Retina Retinal Degeneration Role Stains Structure Structure of retinal pigment epithelium Suggestion Testing Usher Syndrome Type 1B Variant Vision Visual impairment Water Youth base cell motility deaf drug efficacy efficacy testing fluid flow human embryonic stem cell improved induced pluripotent stem cell inhibitor/antagonist insight macromolecule mutant novel optimal treatments protein function retinal progenitor cell water flow

项目摘要

Project Summary The retinal pigment epithelium (RPE) has active transport mechanisms and epithelial junctions that regulate water flow from the apical to the basal surface of the cell. Defects in either of these aspects of RPE function may promote disorders, such as cystoid macular edema (CME), and subsequent visual impairment. Usher Syndrome type 1B (USH1B), which is caused by mutations in MYO7A, includes a relatively high incidence of CME. However, the mechanism of CME in USH1B is unclear. Here, we propose to explore the suggestion that MYO7A is required for normal fluid flow across the RPE. Using RPE cultures, differentiated from induced pluripotent stem cells (iPSCs), derived from USH1B patients, we will test this suggestion and investigate whether loss of MYO7A function results in defective localization of proteins involved in the RPE junctional complex or in transmembrane ion and water flow. Further, we will use these iPSC-RPE cultures to test the efficacy of currently-used medications for CME in increasing water flow across the RPE. These studies will potentially provide novel insight into the retinal function of MYO7A, and a better understanding of impaired vision in USH1B, particularly that resulting from CME.

项目摘要视网膜色素上皮（RPE）具有主动的运输机制和上皮连接调节从根尖到细胞基础表面的水流。任何一个缺陷 RPE功能的这些方面可能会促进疾病，例如囊状黄斑水肿（CME），和随后的视觉障碍。 USHER综合征1B（USH1B），这是由 MyO7a中的突变包括CME的相对较高的发生率。但是，机制 USH1B中的CME尚不清楚。在这里，我们建议探讨需要myo7a的建议对于跨RPE的正常流体流动。使用RPE培养物，与诱导的多能干细胞（IPSC），源自USH1B患者，我们将测试此建议和调查MyO7A功能的损失是否导致涉及蛋白质的定位有缺陷在RPE连接络合物或跨膜离子和水流中。此外，我们将使用这些IPSC-RPE培养物测试当前使用的CME药物的功效增加了RPE的水流。这些研究将有可能提供新颖的见解 Myo7a的视网膜功能，以及对USH1B中视力受损的更好理解，特别是由CME产生的。