Molecular biology and mechanics of cardiac interstitium

描述（由申请方提供）：急性冠状动脉闭塞（CO）导致肌细胞死亡和细胞外基质降解。 大多数在心肌梗塞（MI）中存活的患者具有残余疤痕。 我们将检验以下假设：“冠状动脉闭塞后前48小时内，通过改变梗死心肌的机械特性进行的胶原降解影响了不断发展的瘢痕内随后的胶原合成，从而决定了心室瘢痕的早期（3周）和晚期（6周）结构和功能”。 我们计划：1）表征在CO情况下参与基质金属蛋白酶（MMPs）的早期活化和胶原降解的因素，包括MMPs、纤溶酶和肿瘤坏死因子-α（TNF-α）的机械活化，2）确定早期胶原降解的程度与梗塞区域的材料性质之间的关系，3）确定正在形成的瘢痕中的局部变形与愈合组织中的胶原蛋白合成之间的关系。 我们将研究以下目标。 目标1。 CO后48 h内MMP诱导的胶原降解是由于TNF-α、牵拉、纤溶酶依赖性和独立性对MMP的诱导/激活作用以及胶原纤维的机械破坏。 我们将使用各种药理学方法后，在猪的CO，以确定机械扩张，纤溶酶和TNF-α的作用，对调节胶原蛋白分解产物和MMP活性的血清和心肌样品。 目标二。 CO后48小时内的胶原降解决定了未成熟（3周）胶原性瘢痕的结构和功能特性以及随后的胶原沉积。 在经历CO的猪和小鼠中使用药理学干预，我们将干扰MMP的特异性激活剂或胶原分解活性，并量化I型胶原转录以及缺血区域和早期瘢痕的结构/功能。 目标3： 成熟（6周）心脏疤痕的结构和功能取决于胶原蛋白早期（< 48小时）降解的程度，并且在较小程度上取决于随后的胶原蛋白合成和交联。 使用药理学方法，以减少MMP活性的第一个48小时内CO后，我们提出，纤维化，并因此整体纤维和交叉纤维硬度将在成熟的疤痕衰减，这些事件将被定义的早期损伤的程度，以原来的胶原蛋白基质。 缺血面积和6周瘢痕结构/功能将如目标2中所述进行评估。

DESCRIPTION (provided by applicant): Acute coronary occlusion (CO) results in myocyte cell death and degradation of the extracellular matrix. Most patients who survive a myocardial infarction (Ml) have a residual scar. We will test the hypothesis that: "Collagen degradation within the first 48 h after coronary occlusion by changing the mechanical properties of the infarcted myocardium influences the ensuing collagen synthesis within the evolving scar and thus, determines the early (3 week) and late (6 week) structure and function of the ventricular scar". We plan to: 1) characterize factors involved in the early activation of matrix metalloproteinases (MMPs) and collagen degradation in the setting of CO including the mechanical activation of MMPs, plasmin and tumor necrosis factor-a (TNF-a), 2) determine the relationship between the extent of early collagen degradation and the material properties of the infarcted area and, 3) determine the relationship between local deformation in the evolving scar and collagen synthesis in the healing tissue. We will examine the following aims. Aim 1. MMP induced collagen degradation within 48 h after CO is due to TNF-a, stretch, plasmin dependent and independent inducing/activating actions on MMPs and to the mechanical disruption of collagen fibers. We will use various pharmacological approaches following CO in pigs to determine the role of mechanical distention, plasmin and TNF-a have on modulating collagen breakdown products and MMP activity in serum and in myocardial samples. Aim 2. Collagen degradation within 48 h after CO determines th6 structural and functional properties of the immature (3 week) collagenous scar and the ensuing collagen deposition. Using pharmacological interventions in pigs and mice undergoing CO we will interfere with specific activators of MMPs or collagen breakdown activities and quantify collagen type I transcription as well as the structure/function of the ischemic area and early scar. Aim 3. The structure and function of the mature (6 week) cardiac scar is dependent on the degree of early (< 48 h) degradation of collagen and to a lesser extent on their ensuing synthesis and crosslinking of collagen. Using pharmacological approaches to reduce MMP activity within the first 48 h after CO we propose that fibrosis and as a consequence overall fiber- and cross-fiber stiffness will be attenuated in the mature scar and that these events will be defined by the extent of early damage to the original collagen matrix. lschemic area and 6 week scar structure/function will be assessed as in aim 2.