Role of Blood-Borne Fibroblast Precursors in Ischemic Cardiomyopathy

描述（由申请人提供）：本申请源于过去六年在检查炎症在心脏修复调节中的细胞和分子作用时所做的观察。这些研究旨在了解1)趋化因子调节和2)骨髓源性血源性前体在心脏损伤和修复中的潜在作用。作为这些研究的一部分，我们定义了一种由每日非致死性冠状动脉闭塞和再灌注（I/RC）引起的小鼠纤维化心肌病模型。细胞外超氧化物歧化酶（SOD）的过表达和MCP-1的缺失或抗体抑制均可消除纤维化和心肌功能障碍。我们的数据表明，非适应性纤维化与骨髓源性血源性成纤维细胞前体的摄取有关。冠状动脉疾病的非适应性纤维化和重构显然是心衰和死亡的主要原因之一，即使在没有梗死的情况下。在此资助期研究的主要模型涉及在没有心肌梗死的情况下发展的小鼠纤维化心肌病（I/RC）。该模型为集中研究趋化因子表达失调和骨髓源性血源性成纤维细胞前体的摄取和成熟提供了机会，骨髓源性血源性成纤维细胞前体产生与非适应性心脏纤维化相关的活化成纤维细胞。特异性目的1 -表征和量化介导I/RC中介导非适应性纤维化的血源性成纤维细胞前体的摄取和成熟的因子。特异性目标2 -研究干预的细胞和分子机制，我们已经证明通过特异性地改变血源性前体的生长和/或它们在体内和体外成熟为分泌性成纤维细胞来消除I/RC。我们将研究细胞和分子的后果：a)用血清淀粉样蛋白P治疗和b) Rho激酶（ROCK1）缺失。我们还将研究IP10的作用，IP10是一种CXC趋化因子，通过调节成纤维细胞功能抑制纤维化，并损害梗死后心肌疤痕的形成。

DESCRIPTION (provided by applicant): This application arises from observations made in the last six years while examining the cellular and molecular role of inflammation in the regulation of cardiac repair. The studies were directed at understanding the potential role of 1) chemokine regulation and 2) marrow-derived blood-borne precursors in cardiac injury and repair. As part of these studies, we defined a model of fibrotic cardiomyopathy in the mouse arising from daily, non-lethal coronary occlusion and reperfusion (I/RC). Both the fibrosis and the myocardial dysfunction are obviated by 1) overexpression of extracellular SOD and 2) deletion or antibody inhibition of MCP-1. Our data suggest that the non-adaptive fibrosis is associated with the uptake of marrow-derived blood-borne fibroblast precursors. Non-adaptive fibrosis and remodeling in coronary artery disease is clearly one of the leading causes of heart failure and death even in the absence of infarction. The primary model to be studied in this grant period involves this fibrotic cardiomyopathy (I/RC) in the mouse developing in the absence of myocardial infarction. This model offers the opportunity to concentrate on the role of dysregulation of chemokine expression and the uptake and maturation of the marrow-derived blood- borne fibroblast precursors which generate the activated fibroblasts associated with non-adaptive cardiac fibrosis. Specific Aim 1 - Characterize and quantitate factors mediating the uptake and maturation of blood-derived fibroblast precursors which mediate non-adaptive fibrosis in I/RC. Specific Aim 2 - Examine the cellular and molecular mechanisms of interventions which we have shown to obviate I/RC by specifically altering the growth of blood-derived precursors and/or their maturation into secretory fibroblasts in vivo and in vitro. We will examine the cellular and molecular consequences of: a) treatment with serum amyloid P and b) Rho kinase (ROCK1) deletion. We will also examine the effect of IP10, a CXC chemokine that inhibits fibrosis by modulating fibroblast function and impairs myocardial scar formation following infarction.