Role of MMPs in TGFbeta-induced Cataract Formation

MMPs 在 TGFbeta 诱导的白内障形成中的作用

• 批准号: 8526365
• 负责人: Judith A West-Mays
• 金额: $ 23.05万
• 依托单位: MCMASTER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526365
• 关键词: Adhesions; Anterior; Antibodies; Blindness; Cataract; Cataract Extraction; Cell Adhesion Molecules; Cell-Cell Adhesion; Complication; Crystalline Lens; Data; Developed Countries; Development; Disease; E-Cadherin; Epithelial; Epithelial Cells; Event; Extracapsular; Eye; Fibrosis; Funding; Gelatinase A; Gelatinase B; Goals; Grant; Lead; Link; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Molecular; Mus; Mutant Strains Mice; Myofibroblast; North America; Nuclear Translocation; Operative Surgical Procedures; Organ; Pathway interactions; Play; Prevention; Rattus; Recombinants; Research; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Wild Type Mouse; Work; cost; design; epithelial to mesenchymal transition; in vivo Model; inhibitor/antagonist; lens; lens transparency; morphogens; mouse model; myocardin; prevent; research study; transcription factor; treatment strategy

Epithelial-mesenchymal transition (EMT) has been shown to play an important role in the fibroses of multiple organs and tissues, including the ocular lens, where it contributes to both anterior subcapsular cataracts (ASC) and posterior capsular opacification (PCO), also known as secondary cataract. Increased proliferation of lens epithelial cells (LECs), and EMT of LECs into myofibroblasts, involving a loss of the cell-cell adhesion molecule E-cadherin and an induction in ¿-smooth muscle actin (¿SMA) expression are early events in both ASC and PCO. Transforming growth factor beta (TGF¿) is a pleotropic morphogen that has been shown to induce the EMT of LECs and subsequent formation of ASC, as well as, PCO. Using a previously developed rat lens culture model in which exogenous TGF¿ induces ASC we have shown that treatment with inhibitors to the matrix metalloproteinases (MMP), specifically MMP-2 and MMP-9, suppresses TGF¿-induced cataractous changes, including EMT. Studies from the previous grant period further show that these two MMPs likely work cooperatively and/or redundantly in the development of these cataracts. For example, using a model of ASC involving the delivery of AdTGF¿ to the eye we have shown that MMP-9 KO mice develop cataracts, albeit they are delayed compared to wild-type mice. Thus, inhibiting both MMPs may be required to prevent EMT and subsequent cataractogenesis. The potential mechanism by which these MMPs mediate EMT and cataract formation was identified during the previous funding period and involves disruption of E-cadherin. Preliminary data suggests that disruption and shedding of E-cadherin results in downstream signaling events linked to EMT including nuclear translocation of ¿-catenin and the myocardin-related transcription factor (MRTF-A). However, the requirement for these signaling intermediates in ASC and PCO and how MMPs are involved is not known. In the current proposal we investigate these TGF¿-mediated signaling pathways using multiple ex vivo and in vivo models of ASC and PCO. In addition, we outline experiments that will directly determine the unique and/or cooperative roles of MMP-2 and MMP-9 in ASC formation. Ultimately, our goal is to define the TGF¿- mediated pathways controlling EMT and fibrosis in ASC and PCO in order to design therapeutics for mitigating these diseases.

上皮-间质转化（EMT）已被证明在纤维化中起重要作用， 多个器官和组织，包括眼透镜，在那里它有助于前囊下 白内障（ASC）和后囊膜混浊（PCO），也称为继发性白内障。 透镜上皮细胞（LEC）增殖增加，LEC向肌成纤维细胞的EMT，涉及 细胞间粘附分子E-钙粘蛋白的丢失和平滑肌肌动蛋白的诱导 SMA表达是ASC和PCO的早期事件。转化生长因子β（TGF β）是 一种多效性形态发生素，已显示可诱导LEC的EMT和随后的 ASC以及PCO。使用先前开发的大鼠透镜培养模型，其中外源性TGF？ 诱导ASC我们已经表明用基质金属蛋白酶（MMP）抑制剂治疗， 特别是MMP-2和MMP-9，抑制TGF β诱导的白内障变化，包括EMT。 上一个资助期的研究进一步表明，这两种MMPs可能会合作 和/或多余地参与这些白内障的发展。例如，使用ASC模型 涉及将AdTGF β递送到眼睛，我们已经表明MMP-9 KO小鼠发生白内障， 尽管与野生型小鼠相比它们被延迟。因此，可能需要抑制两种MMP， 预防EMT和随后的白内障发生。这些基质金属蛋白酶的潜在机制 在上一个资助期间确定了介导的EMT和白内障形成， E-钙粘蛋白的破坏。初步数据表明，E-钙粘蛋白的破坏和脱落导致 在与EMT相关的下游信号传导事件中，包括连环蛋白的核转位， 心肌素相关转录因子（MRTF-A）。然而，这些信令的要求 ASC和PCO中的中间体以及MMPs如何参与尚不清楚。在目前的提案中，我们 使用多种离体和体内ASC模型研究这些TGF β介导的信号通路 和PCO。此外，我们概述了将直接确定独特和/或 MMP-2和MMP-9在ASC形成中的协同作用。最终，我们的目标是定义TGF？ 介导的途径控制ASC和PCO中的EMT和纤维化，以便设计治疗方法， 减轻这些疾病。