Role of Clusterin in Aqueous Humor Outflow Physiology

凝聚素在房水流出生理学中的作用

• 批准号: 9817242
• 负责人: Padmanabhan Paranji Pattabiraman
• 金额: $ 40.04万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2019-10-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817242
• 关键词: Adenoviruses; Anterior; Aqueous Humor; Attenuated; Biological Assay; Blindness; Caspase; Cells; Clinical; Collagen; Complex; Cytoskeleton; Data; Deposition; Development; Disease Progression; Drainage procedure; Elastin; Event; Exhibits; Extracellular Matrix; Extracellular Matrix Degradation; Eye; Eye Development; Eye diseases; Fibronectins; Fibrosis; Future; Glaucoma; Homeostasis; Human; In Vitro; Individual; Knowledge; Lead; Link; Liquid substance; Measures; Mediating; Metalloproteases; Modeling; Molecular; Molecular Chaperones; Mus; Ocular Hypertension; Outcome; Pathologic; Pathway interactions; Perfusion; Pharmacology; Physiologic Intraocular Pressure; Physiological; Physiology; Play; Primary Open Angle Glaucoma; Production; Proteins; Proteomics; Public Health; Receptor Signaling; Recombinants; Regulation; Research; Resistance; Risk Factors; Role; Signal Transduction; Structure; Testing; Text; Therapeutic; Time; Tissues; Trabecular meshwork structure; Transforming Growth Factor Beta 2; United States; Wild Type Mouse; anterior chamber; aqueous; base; cathepsin K; inhibitor/antagonist; innovation; insight; knock-down; novel; novel therapeutics; prevent; receptor; secretory protein; small hairpin RNA; stem; stressor; sulfated glycoprotein 2; therapeutic target

Project Summary: Strong correlations exist between excessive structural changes in the trabecular meshwork (TM)- juxtacanalicular tissue (JCT) of the aqueous humor (AH) outflow pathway. Increased outflow resistance leads to elevated intraocular pressure (IOP), which is a major risk factor for primary open angle glaucoma (POAG). POAG is the second leading cause of blindness in the United States. Lowering IOP significantly halts the progression of the disease. The molecular players and mechanisms leading to the excessive extracellular matrix (ECM) build-up and elevated IOP are complex and little understood. Preliminary data in support of this proposal identifies clusterin, a secretory chaperone protein, as an important regulator of IOP. We have identified that clusterin and its downstream target cathepsin k (CTSK) regulates of cell-cytoskeleton and cell-ECM interactions in the aqueous humor outflow pathway tissues. Based on this compelling evidence, we propose the CENTRAL HYPOTHESIZE that clusterin plays a critical role in the IOP homeostasis and disruption of clusterin function can contribute to POAG. The proposed study will mechanistically understand the role of clusterin in aqueous outflow drainage and in POAG and offer new therapeutic opportunities. The scientific premise for this hypothesis stems from our preliminary data, which shows that loss of clusterin results in increased fibrogenic activity in the TM outflow pathway and constitutive expression of clusterin resulting in lowering of IOP by decreasing cell-cytoskeleton and cell-ECM interactions. Given the convincing evidence for a key role played by clusterin in the TM, this project will carefully examine the function of clusterin with three different aims. Aim 1 will test the hypothesis that the loss of clusterin in the trabecular outflow pathway results in elevated IOP due to defective ECM degradation and clearance. Aim 2 will test the hypothesis that clusterin requires CTSK production and activation to lower IOP. Aim 3 will test the hypothesis that direct delivery of clusterin into the anterior chamber reverses pathological ocular hypertension. The proposed research is innovative because we have identified two key proteins - clusterin and its downstream target cathepsin K in the regulation of IOP via modulation of ECM turnover and remodeling. Key insights into the unknown functions of clusterin and cathepsin K will help in developing modifiable therapeutic targets in the future to lower IOP. Relevance to public health: Better understanding of the molecular mechanisms regulating homeostasis of aqueous humor outflow resistance will provide novel clinical strategies to reduce IOP elevation and prevent vision loss.

项目总结: