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中在检查炎症在心脏修复调节中的细胞和分子作用时进行的观察。这些研究旨在了解1）趋化因子调节和2）骨髓来源的血液传播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，我们在小鼠中定义了一种由每日非致死性冠状动脉闭塞和再灌注（I/RC）引起的纤维化心肌病模型。纤维化和心肌功能障碍均通过1）细胞外SOD的过表达和2）MCP-1的缺失或抗体抑制来避免。我们的数据表明，非适应性纤维化与骨髓来源的血源性成纤维细胞前体的摄取有关。冠状动脉疾病中的非适应性纤维化和重塑显然是心力衰竭和死亡的主要原因之一，即使在没有梗死的情况下。在本授权期内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中的这种纤维化心肌病（I/RC）。该模型提供了关注趋化因子表达失调的作用以及骨髓来源的血源性成纤维细胞前体的摄取和成熟的机会，所述骨髓来源的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的成纤维细胞。具体目标1 -表征和定量介导I/RC中非适应性纤维化的血液来源的成纤维细胞前体的摄取和成熟的因子。具体目标2 -检查干预的细胞和分子机制，我们已经表明，通过特异性改变血液来源的前体细胞的生长和/或它们在体内和体外成熟为分泌性成纤维细胞，以达到治疗REMOI/RC的目的。我们将检查以下两种情况的细胞和分子结果：a）用血清淀粉样蛋白P治疗和B）Rho激酶（ROCK 1）缺失。我们还将研究IP 10的作用，IP 10是一种CXC趋化因子，通过调节成纤维细胞功能抑制纤维化，并损害梗死后心肌瘢痕形成。

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.