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: 10006573
• 负责人: Padmanabhan Paranji Pattabiraman
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006573
• 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; 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.

项目概要： 小梁网（TM）过度结构变化之间存在强相关性， 房水（AH）流出途径的小管组织（JCT）。流出阻力增加 导致眼内压（IOP）升高，这是原发性开角型青光眼的主要风险因素 青光眼（POAG）。POAG是美国第二大致盲原因。降低IOP 能显著阻止疾病的发展分子参与者和机制导致了 过度的细胞外基质（ECM）积聚和升高的IOP是复杂的，并且很少被理解。 支持这一提议的初步数据确定丛生蛋白（一种分泌伴侣蛋白）是一种 IOP的重要调节剂。我们已经鉴定了聚集蛋白及其下游靶蛋白组织蛋白酶K （CTSK）调节房水流出途径中的细胞-细胞骨架和细胞-ECM相互作用 组织中基于这一令人信服的证据，我们提出了一个中心假设， 在眼内压稳态中起着关键作用， 为POAG做出贡献。这项拟议的研究将从机制上了解丛生蛋白在以下方面的作用： 房水流出引流和POAG，并提供新的治疗机会。 这一假设的科学前提源于我们的初步数据，这些数据表明， 丛生蛋白的增加导致TM流出途径的纤维化活性增加， 通过减少细胞骨架和细胞外基质降低眼压 交互.鉴于clusterin在TM中发挥关键作用的令人信服的证据，本项目将 用三个不同的目标仔细检查clusterin的功能。目标1将检验假设 小梁流出通道中聚集蛋白的丢失导致IOP升高， ECM退化和间隙缺陷。目标2将检验以下假设： 需要CTSK的产生和活化以降低IOP。目标3将检验以下假设 将丛生素直接递送到前房中可逆转病理性眼 高血压 这项研究具有创新性，因为我们已经确定了两种关键蛋白质--簇蛋白和 其下游靶点组织蛋白酶K通过调节ECM周转调节IOP， 重塑对簇蛋白和组织蛋白酶K未知功能的关键见解将有助于 在未来开发可修改的治疗靶点以降低IOP。 与公共卫生的相关性： 更好地理解调节房水内稳态的分子机制 外流阻力将提供新的临床策略来降低IOP升高和防止视力丧失。