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对炎症在心脏修复调节中的细胞和分子作用的观察。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，我们定义了一种由日常非致死性冠状动脉闭塞和再灌注(I/RC)引起的小鼠纤维性心肌病模型。通过1)细胞外超氧化物歧化酶的过度表达和2)单核细胞趋化蛋白-1的缺失或抗体抑制，可以避免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来源的血源性成纤维细胞前体细胞的摄取有关。冠状动脉疾病中的非适应性纤维化和重构显然是心力衰竭和死亡的主要原因之一，即使在没有梗塞的情况下也是如此。在这一资助期间要研究的主要模型包括在没有心肌梗死的情况下发展的小鼠的这种纤维性心肌病(I/RC)。该模型提供了集中研究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作用，这些前体产生了与非适应性心脏纤维化相关的激活的成纤维细胞。具体目标1-表征和量化介导I/RC中非适应性纤维化的血源性成纤维细胞前体细胞摄取和成熟的因素。特定目标2-研究干预的细胞和分子机制，我们已经证明，通过在体内和体外特异性地改变血源性前体细胞的生长和/或其成熟为分泌型成纤维细胞，可以消除I/RC。我们将研究：a)血清淀粉样蛋白P和b)Rho激酶(ROCK1)缺失治疗的细胞和分子后果。我们还将研究IP10的作用，这是一种CXC趋化因子，通过调节成纤维细胞功能来抑制纤维化，并损害心肌梗死后瘢痕的形成。

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.