Role of MMPs in TGFbeta-induced Cataract Formation
MMPs 在 TGFbeta 诱导的白内障形成中的作用
基本信息
- 批准号:8188198
- 负责人:
- 金额:$ 24.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AdhesionsAnteriorAntibodiesBlindnessCataractCataract ExtractionCell Adhesion MoleculesCell-Cell AdhesionComplicationCrystalline LensDataDeveloped CountriesDevelopmentDiseaseE-CadherinEpithelialEpithelial CellsEventExtracapsularEyeFibrosisFundingGelatinase AGelatinase BGoalsGrantLeadLinkMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMediatingMediator of activation proteinMesenchymalModelingMolecularMusMutant Strains MiceMyofibroblastNorth AmericaNuclear TranslocationOperative Surgical ProceduresOrganPathway interactionsPlayPreventionRattusRecombinantsResearchRoleSignal PathwaySignal TransductionSmooth Muscle Actin Staining MethodTestingTherapeuticTissuesTransforming Growth Factor betaWild Type MouseWorkcostdesignepithelial to mesenchymal transitionin vivo Modelinhibitor/antagonistlenslens transparencymorphogensmouse modelmyocardinpreventresearch studytranscription factortreatment strategy
项目摘要
DESCRIPTION (provided by applicant): 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 Ad TGF? 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 application 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.
PUBLIC HEALTH RELEVANCE: Loss of transparency of the lens, or cataract, is the leading cause of blindness worldwide despite the availability of effective surgery in developed countries. Extracapsular cataract extraction is the most frequently performed surgical procedure in North America, costing over 3.5 billion dollars each year, and can frequently lead to complications such as the development of secondary cataract (posterior capsular opacification (PCO). Thus, an understanding of the cellular and molecular mechanisms regulating the normal and pathological differentiation of the lens is necessary in order to develop therapeutic strategies for the treatment and/or prevention of cataracts. In the proposed research we will investigate the cell signaling mechanisms responsible for two fibrotic cataracts, anterior subcapsular cataracts (ASC) and PCO and further determine how these mechanisms can be inhibited. Specifically we will focus on those pathways mediated by transforming growth factor beta (TGF?) and the matrix metalloproteinases (MMPs) since both of have been implicated in these cataracts. Ultimately, it is hoped that the data obtained from the proposed studies will lead to therapeutic strategies for mitigating cataract formation.
描述(由申请人提供):上皮间质转化(EMT)已被证明在多个器官和组织的纤维化中发挥重要作用,包括眼晶状体,它导致前囊下白内障(ASC)和后囊下白内障混浊(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-钙粘蛋白的丢失和 β-平滑肌肌动蛋白 (?SMA) 表达的诱导,是 ASC 的早期事件和 PCO。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 ASC 和 PCO 的形成。使用先前开发的大鼠晶状体培养模型,其中外源性TGF?诱导 ASC 我们已经证明,用基质金属蛋白酶 (MMP) 抑制剂(特别是 MMP-2 和 MMP-9)治疗可以抑制 TGF? -引起的白内障变化,包括EMT。上一资助期的研究进一步表明,这两种 MMP 可能在这些白内障的发展中协同和/或冗余地发挥作用。例如,使用涉及 Ad TGF 递送的 ASC 模型?从肉眼来看,我们已经证明 MMP-9 KO 小鼠会出现白内障,尽管与野生型小鼠相比,白内障发生的时间较晚。因此,可能需要抑制这两种 MMP 来预防 EMT 和随后的白内障发生。这些 MMP 介导 EMT 和白内障形成的潜在机制在之前的资助期间已被确定,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会导致与 EMT 相关的下游信号事件,包括 β-连环蛋白和心肌素相关转录因子 (MRTF-A) 的核转位。然而,ASC 和 PCO 中对这些信号中间体的需求以及 MMP 如何参与尚不清楚。在当前的应用中我们研究这些TGF? -使用 ASC 和 PCO 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 MMP-2 和 MMP-9 在 ASC 形成中的独特和/或协同作用的实验。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,以便设计减轻这些疾病的疗法。
公共健康相关性:尽管发达国家可以进行有效的手术,但晶状体透明度丧失或白内障是全世界失明的主要原因。囊外白内障摘除术是北美最常进行的外科手术,每年花费超过 35 亿美元,并且经常会导致继发性白内障(后囊膜混浊 (PCO))等并发症。因此,了解细胞为了制定治疗和/或预防白内障的治疗策略,调节晶状体正常和病理分化的分子机制是必要的。在拟议的研究中,我们将研究导致两种纤维化的细胞信号传导机制。白内障、前囊下白内障 (ASC) 和 PCO,并进一步确定如何抑制这些机制,具体来说,我们将重点关注由转化生长因子 β (TGF?) 和基质金属蛋白酶 (MMP) 介导的途径,因为这两种途径都受到牵连。最终,希望从拟议研究中获得的数据能够制定出减轻白内障形成的治疗策略。
项目成果
期刊论文数量(0)
专著数量(0)
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Judith A West-Mays其他文献
Judith A West-Mays的其他文献
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{{ truncateString('Judith A West-Mays', 18)}}的其他基金
Role of transcription factor activating protein-2 beta (AP-2β) in corneal epithelial cell fate determination and stratification
转录因子激活蛋白 2 beta (AP-2β) 在角膜上皮细胞命运决定和分层中的作用
- 批准号:
10510823 - 财政年份:2022
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$ 24.27万 - 项目类别:
Role of transcription factor activating protein-2 beta (AP-2β) in corneal epithelial cell fate determination and stratification
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10683400 - 财政年份:2022
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Role of Matrix Metalloproteinases in Subcapsular Cataract Formation
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7386538 - 财政年份:2006
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$ 24.27万 - 项目类别:
Role of Matrix Metalloproteinases in Subcapsular Cataract Formation
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7589653 - 财政年份:2006
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$ 24.27万 - 项目类别:
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:
8323802 - 财政年份:2006
- 资助金额:
$ 24.27万 - 项目类别:
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 - 财政年份:2006
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$ 24.27万 - 项目类别:
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- 批准号:
7024380 - 财政年份:2006
- 资助金额:
$ 24.27万 - 项目类别:
Role of Matrix Metalloproteinases in Subcapsular Cataract Formation
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- 批准号:
7825296 - 财政年份:2006
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$ 24.27万 - 项目类别:
Role of Matrix Metalloproteinases in Subcapsular Cataract Formation
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7186673 - 财政年份:2006
- 资助金额:
$ 24.27万 - 项目类别:
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 - 财政年份:2006
- 资助金额:
$ 24.27万 - 项目类别:
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