Role of Clusterin in Aqueous Humor Outflow Physiology

凝聚素在房水流出生理学中的作用

基本信息

批准号：
10240478
负责人：
Padmanabhan Paranji Pattabiraman
金额：
$ 38.44万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/10240478
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

项目摘要

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.

项目摘要：小梁网（TM）的过度结构变化之间存在很强的相关性 - 水性幽默（AH）流出途径的近去层组织（JCT）。增加了流出阻力导致眼内压（IOP）升高，这是主要开放角度的主要危险因素青光眼（POAG）。 POAG是美国失明的第二大主要原因。降低IOP 显着停止了疾病的进展。分子参与者和机制导致过度的细胞外基质（ECM）堆积和升高的IOP是复杂的，几乎没有理解。支持该提案的初步数据确定簇蛋白是一种分泌的伴侣蛋白，作为一种 IOP的重要调节器。我们已经确定了簇蛋白及其下游目标组织蛋白酶K （CTSK）在水性幽默流出途径中调节细胞细胞骨架和细胞ECM相互作用组织。基于这个令人信服的证据，我们提出了中心假设的簇蛋白在IOP稳态中起着至关重要的作用，簇蛋白功能的破坏可以为Poag做出贡献。拟议的研究将机械理解簇蛋白在水流排水和POAG，并提供新的治疗机会。该假设的科学前提源于我们的初步数据，这表明损失簇蛋白的纤维化活性增加了TM流出途径和本构型簇蛋白的表达通过降低细胞骨架和细胞ECM导致IOP降低IOP 互动。考虑到Clusterin在TM中扮演的关键角色的令人信服的证据，该项目将仔细检查簇蛋白的功能，三个不同的目标。 AIM 1将检验假设小梁流出途径中簇蛋白的损失导致IOP升高 ECM降解和清除有缺陷。 AIM 2将检验簇蛋白的假设需要CTSK生产和激活以降低IOP。 AIM 3将检验以下假设将簇蛋白直接递送到前腔中逆转病理眼高血压。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 - 簇蛋白和它通过调节ECM周转率和重塑。对簇蛋白和组织蛋白酶K的未知功能的关键见解将有助于将来开发可修改的治疗靶标，以降低IOP。与公共卫生有关：更好地理解调节水性幽默稳态的分子机制排阻将提供新的临床策略，以降低IOP升高并防止视力丧失。