Molecular Mechanisms of Outflow Segmentation and Intraocular Pressure Homeostasis

流出分段和眼压稳态的分子机制

• 批准号: 10478291
• 负责人: TED S ACOTT
• 金额: $ 33.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478291
• 关键词: Affect; Anabolism; Anterior; Behavior; Binding; Cells; Characteristics; Data; Disease; Endothelium; Extracellular Matrix; Extracellular Matrix Proteins; Eye; Funding; Glaucoma; Homeostasis; Human; Knowledge; Mechanics; Messenger RNA; Molecular; Organ Culture Techniques; Outcome Study; Pathway interactions; Peptides; Perfusion; Persons; Physiologic Intraocular Pressure; Process; Protein Biosynthesis; Protein Overexpression; Proteomics; RNA Interference; Regulation; Resistance; Risk Factors; Role; Stretching; Structure of sinus venosus of sclera; Testing; Therapeutic; Tissues; Trabecular meshwork structure; aqueous; functional restoration; inhibitor; knock-down; laser capture microdissection; mRNA Expression; molecular subtypes; novel; pressure; protein expression; protein function; response

Project Summary Glaucoma is a major blinding disease. The primary risk factor and only current treatment target for all types of glaucoma is elevated intraocular pressure (IOP). We have identified a robust IOP homeostatic mechanism in which sustained pressure deviations are sensed as mechanical stretching/distortion by cells within the juxtacanalicular (JCT) region of the outflow pathway and corrective adjustments are made to the outflow resistance which restore IOP to appropriate levels. This appears to be a key reason that most people do not develop glaucoma. We recently showed that glaucomatous anterior segments cannot execute a normal IOP homeostatic response. Outflow is segmental around the circumference of the eye with regions of high flow (HF) intermediate flow (IF) and low flow (LF). We recently showed that glaucomatous eyes have more LF regions than normal eyes. This proposal is directed at understanding these two phenomena, IOP homeostasis and outflow segmentation, and exploiting this understanding to correct the glaucomatous deficiencies in them. To begin understanding the IOP homeostatic process and outflow segmentation, we evaluated molecular distribution differences between HF and LF regions of human anterior segments that had been perfused at 1x (normal) or 2x (homeostatic response) pressures. We selected a subset of the molecular differences that seemed most relevant to these processes; they were mostly extracellular matrix (ECM) proteins that function in ECM organization and remodeling. We will refine their distributions, evaluate their regional biosynthesis/dynamics rates, use RNAi silencing to knockdown their levels, interfere directly with their binding interactions, and conduct a few select protein overexpression studies. Primary readouts will be outflow segmentation changes and outflow facility changes in perfused human anterior segment organ culture. Next we will obtain the same molecular distribution data for glaucomatous eyes and using the most effective RNAi silencing and binding interaction perturbations from normal and apply them to glaucomatous eyes. The point will be to modify outflow segmentation and IOP homeostatic responsiveness in diseased tissue to restore function.

项目总结

项目成果

Estimating Human Trabecular Meshwork Stiffness by Numerical Modeling and Advanced OCT Imaging.

• DOI: 10.1167/iovs.17-22175
• 发表时间: 2017-09-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Wang K;Johnstone MA;Xin C;Song S;Padilla S;Vranka JA;Acott TS;Zhou K;Schwaner SA;Wang RK;Sulchek T;Ethier CR
• 通讯作者: Ethier CR