Maladaptive Remodeling in Aging Myocardium

衰老心肌的适应不良重塑

• 批准号: 8738062
• 负责人: FRANCIS G SPINALE
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738062
• 关键词: Address; Adverse effects; Affect; Aging; Animals; Binding Proteins; Cells; Clinical; Computer Simulation; Cytoskeleton; Diagnosis; Enzymes; Event; Extracellular Matrix; Family suidae; Fibroblasts; Fibrosis; Gelatinase A; Gene Transfer Techniques; Geometry; Hand; Heart; Heart failure; Heterogeneity; Hyaluronic Acid; Hydrogels; Infarction; Injection of therapeutic agent; Interruption; Ischemia; Laboratory Study; Left; Left Ventricular Remodeling; Maintenance; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Methods; Microdialysis; Modeling; Myocardial; Myocardial Infarction; Myocardium; Oral cavity; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Peptide Mapping; Performance; Pharmaceutical Preparations; Play; Process; Reperfusion Therapy; Role; Signal Transduction; Signaling Molecule; Staging; Stress; Structural Protein; Structure; System; Techniques; Testing; Time; Transforming Growth Factor beta; Transgenic Organisms; Ventricular; base; cell type; combinatorial; design; human MMP14 protein; improved; in vivo; interstitial; novel; overexpression; patient population; prevent; public health relevance; therapeutic target; translational approach

DESCRIPTION (provided by applicant): Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events, invariably occurs following a myocardial infarction (MI) and contributes to clinical outcomes. The ECM plays a critical role in the maintenance of LV geometry and function, and increased induction of the ECM proteolytic enzymes, the matrix metalloproteinases (MMPs) occur with MI and contribute to LV remodeling. We have established that a unique MMP type, the membrane type-1 MMP (MT1-MMP), is increased following MI, and that overexpression accelerates post-MI remodeling. Recent studies from this laboratory and others have identified that MT1-MMP may actually facilitate ECM synthesis by processing profibrotic signaling molecules, such as transforming growth factor-beta (TGF). Our new results have identified that MT1-MMP processes the latent TGF binding protein-1 (LTBP-1), potentially augmenting ECM synthesis/accumulation. However, to move the field forward in terms of cause-effect between MT1-MMP induction and adverse LV remodeling, as well as establishing a therapeutic target, will require novel transgenic constructs and most importantly targeted, selective MT1-MMP inhibition. In this project continuation, we will move our basic discoveries forward and utilize ou newly developed MT1-MMP targeting techniques in order to test the hypothesis that while MT1-MMP activation occurs within the MI region as well as the remote viable myocardium, distinctly different proteolytic events occur - favoring myocardial matrix instability within the MI region an accelerated fibrosis within the remote region. Thus, selective targeting of MT1-MMP induction in a region, temporal, and cell specific fashion will directly alter the course of LV remodeling. The following aims will be addressed: (1) Discovery of MT1-MMP Heterogeneity: Demonstrate a regional heterogeneity in myocardial MT1-MMP substrate processing and establish that region specific fibroblast transformation and persistent MT1-MMP expression occurs. (2) Establishing MT1-MMP Mechanisms by Transgenesis: Establish cell specific targeting of MT1-MMP will alter the course of LV remodeling post MI. We will utilize both myocardial and fibroblast specific alterations in MT1-MMP levels following MI. (3) Demonstrating MT1-MMP as a Therapeutic Target: Using a validated regional injection method, whereby the MT1-MMP inhibitor is contained within a hydrogel, establish that selective and regional MT1-MMP inhibition will alter the course of adverse LV remodeling. Through a stepwise and combinatorial translational approach, a proteolytic pathway contributing to heterogeneous LV remodeling post-I/R will be established and will identify both interstitial signaling and intracellular pathways that can serve as potential therapeutic targets to favorably modify this process. These findings hold relevance to ECM remodeling/fibrosis pathways in general and are of particular relevance to adverse LV remodeling which occurs within the VA patient population.

描述（由申请人提供）： 左心室（LV）重塑是细胞和细胞外基质（ECM）事件的总结，总是在心肌梗塞（MI）之后发生，并有助于临床结果。 ECM在维持LV几何和功能以及增加ECM蛋白水解酶的诱导中起着至关重要的作用，基质金属蛋白酶（MMP）与MI一起出现并有助于LV重塑。我们已经确定，MI后增加了独特的MMP类型，即膜型1MMP（MT1-MMP），并且过表达加速了MI后MI重塑。该实验室和其他人的最新研究表明，MT1-MMP实际上可能通过处理纤维纤维化信号分子（例如转化生长因子-BETA（TGF））来促进ECM合成。我们的新结果已经确定MT1-MMP处理潜在的TGF结合蛋白-1（LTBP-1），可能会增加ECM合成/积累。但是，要以MT1-MMP诱导与不良LV重塑以及建立治疗靶标之间的原因效应向前推动该领域，将需要新的转基因构建体，最重要的是针对性的，选择性的，选择性的MT1-MMP抑制。在这个项目延续中，我们将向前进并利用新开发的MT1-MMP靶向技术，以检验以下假设：尽管MT1-MMP激活发生在MI区域内以及远程可行的心肌内以及巨大不同的蛋白水解事件，但在MI区域内发生了明显不同的蛋白质水解事件，而在MI区域内发生了远程依次的远程依赖。因此，选择性靶向MT1-MMP诱导区域，时间和细胞特异性方式将直接改变LV重塑的过程。将解决以下目的：（1）发现MT1-MMP异质性：在心肌MT1-MMP底物处理中证明了区域异质性，并确定该区域特异性成纤维细胞转换和持续的MT1-MMP表达发生。 （2）通过转基因建立MT1-MMP机制：建立MT1-MMP的细胞特异性靶向将改变MI后LV重塑的过程。 MI后，我们将利用MT1-MMP水平的心肌和成纤维细胞特异性变化。 （3）证明MT1-MMP作为治疗靶点：使用经过验证的区域注射方法，其中MT1-MMP抑制剂包含在水凝胶中，确定选择性和区域MT1-MMP抑制作用将改变不良LV重塑的过程。通过逐步和组合的翻译方法，将建立有助于异质LV重塑后I/R的蛋白水解途径，并将确定可以使用的间质信号传导和细胞内途径 作为潜在的治疗靶标，可以有利地修改此过程。这些发现与ECM重塑/纤维化途径相关，并且与VA患者人群中发生的不良LV重塑特别相关。