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: 8716760
• 负责人: Judith A West-Mays
• 金额: $ 23.78万
• 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/8716760
• 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发挥重要作用 多个器官和组织，包括眼晶状体，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。 晶状体上皮细胞 (LEC) 增殖增加，以及 LEC 向肌成纤维细胞的 EMT，涉及 细胞间粘附分子 E-钙粘蛋白的损失和 ¿ 的诱导- 平滑肌肌动蛋白 (¿SMA) 表达是 ASC 和 PCO 中的早期事件，转化生长因子 β (TGF¿) 是。 一种多效性形态发生素，已被证明可以诱导 LEC 的 EMT 以及随后形成 ASC 以及 PCO 使用先前开发的大鼠晶状体培养模型，其中外源 TGF¿ 诱导 ASC 我们已经证明用基质金属蛋白酶 (MMP) 抑制剂进行治疗， 特别是 MMP-2 和 MMP-9，抑制 TGF¿ -引起的白内障变化，包括EMT。 上一个资助期的研究进一步表明，这两个 MMP 可能协同工作 和/或在这些白内障的发展中重复使用例如，使用ASC模型。 涉及 AdTGF 的传递¿从眼睛来看，我们已经证明 MMP-9 KO 小鼠会患上白内障， 尽管与野生型小鼠相比，它们出现延迟，因此可能需要抑制这两种 MMP。 这些 MMP 预防 EMT 和随后的白内障发生的潜在机制。 在上一个资助期间发现了介导 EMT 和白内障形成的因素，并涉及 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。 与 EMT 相关的下游信号事件，包括 ¿ 的核转位-连环蛋白和 然而，心肌素相关转录因子（MRTF-A）需要这些信号传导。 ASC 和 PCO 中的中间体以及 MMP 如何参与目前的提案中我们尚不清楚。 研究这些 TGF¿ - 使用 ASC 的多个离体和体内模型介导的信号通路 此外，我们概述了将直接确定独特和/或的实验。 MMP-2 和 MMP-9 在 ASC 形成中的合作作用最终，我们的目标是定义 TGF¿ - 控制 ASC 和 PCO 中 EMT 和纤维化的介导途径，以便设计治疗方法 减轻这些疾病。