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.

项目概要： 小梁网 (TM) 的过度结构变化之间存在很强的相关性 - 房水（AH）流出途径的近小管组织（JCT）。流出阻力增加 导致眼内压（IOP）升高，这是原发性开角的主要危险因素 青光眼（POAG）。 POAG 是美国第二大失明原因。降低眼压 显着阻止疾病的进展。导致这一现象的分子参与者和机制 细胞外基质（ECM）过度堆积和眼压升高非常复杂，但人们对此知之甚少。 支持该提案的初步数据表明，簇蛋白（一种分泌伴侣蛋白）是一种 IOP 的重要调节因子。我们已经确定了 clusterin 及其下游目标组织蛋白酶 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。基于这一令人信服的证据，我们提出了中心假设：聚类 在 IOP 稳态中起着关键作用，并且聚集蛋白功能的破坏可以 为 POAG 做出贡献。拟议的研究将从机制上理解凝聚素在 房水流出引流和 POAG 提供了新的治疗机会。 这一假设的科学前提源于我们的初步数据，该数据表明损失 簇蛋白的增加导致 TM 流出途径和组成性纤维化活性增加 凝聚素的表达通过减少细胞骨架和细胞 ECM 来降低眼压 互动。鉴于有令人信服的证据表明 clusterin 在 TM 中发挥关键作用，该项目将 仔细检查簇蛋白的功能，具有三个不同的目的。目标 1 将检验假设 小梁流出通路中簇蛋白的丢失导致眼压升高，原因是 有缺陷的 ECM 降解和清除。目标 2 将检验聚类的假设 需要 CTSK 生成和激活以降低 IOP。目标 3 将检验以下假设： 直接将簇蛋白输送到前房可逆转病理性眼病 高血压。 拟议的研究具有创新性，因为我们已经确定了两种关键蛋白质——簇蛋白和 其下游目标组织蛋白酶 K 通过调节 ECM 周转来调节 IOP 重塑。对簇蛋白和组织蛋白酶 K 的未知功能的重要见解将有助于 未来开发可修改的治疗目标以降低眼压。 与公共卫生的相关性： 更好地理解调节房水稳态的分子机制 流出阻力将为降低眼压升高和防止视力丧失提供新的临床策略。