Role of Clusterin in Aqueous Humor Outflow Physiology

项目总结： 小梁网(TM)的过度结构变化之间存在很强的相关性。 房水(AH)流出通道旁组织(JCT)。增加流出阻力 导致眼压升高(IOP)，这是导致原发开角的主要危险因素 青光眼(POAG)。在美国，POAG是导致失明的第二大原因。降低眼压 显著地阻止了疾病的发展。导致全球变暖的分子因素和机制 细胞外基质(ECM)过度积聚和眼压升高是复杂且鲜为人知的问题。 支持这一提议的初步数据表明，簇蛋白是一种分泌伴侣蛋白，是一种 眼压的重要调节剂。我们已经确定了Clusterin及其下游靶标组织蛋白k (CTSK)对房水流出通路中细胞-细胞骨架和细胞-ECM相互作用的调节 纸巾。基于这一令人信服的证据，我们提出了中心假设 在眼压动态平衡和聚集素功能紊乱中起关键作用 为POAG捐款。这项拟议的研究将机械地理解聚集素在 房水外流引流和开角型青光眼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，这些数据表明 聚集素导致TM流出途径和成分中的纤维化活性增加 聚集素的表达通过减少细胞骨架和细胞外基质而降低眼压 互动。鉴于有令人信服的证据表明Clusterin在TM中发挥了关键作用，该项目将 仔细研究聚集素的功能，有三个不同的目的。目标1将检验这一假设 小梁流出道中聚集素的丢失导致眼压升高 ECM降解和清除有缺陷。目标2将检验以下假设：集群 需要CTSK的产生和激活来降低眼压。目标3将检验这一假设 聚集素直接注入前房逆转病理性眼球 高血压。 这项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--Clusterin和 其下游靶点组织蛋白K通过调节细胞外基质的周转和调节眼压 改建。对Clusterin和Cathepsin K未知功能的关键见解将有助于 未来开发可修改的治疗靶点以降低眼压。 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 流出阻力将为降低眼压升高和预防视力丧失提供新的临床策略。

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.