Fibroblasts and Mononuclear Fibrogenic Cells Drive Right Ventricular Pulmonary Ar

描述（由申请人提供）：右心室（RV）衰竭是肺动脉高压（PAH）患者最常见的死亡原因。目前，对PAH环境下RV失效的机制知之甚少。越来越多的人认识到，这不仅仅是由于远端肺微血管疾病和高肺血管阻力，而是由于肺循环和右心室之间复杂的相互作用。众所周知，炎症对大血管和小血管重构的改变以及RV功能障碍都有重要作用，特别是在硬皮病相关的PAH （SSc-PAH）中。循环单核纤维化细胞与炎症、血管重塑和右心室功能障碍有关。我们已经证明，PAH患者和动物模型中的成纤维细胞获得激活和表观遗传改变的表型，能够产生微环境，促进循环单核纤维化细胞的募集和激活，这些细胞直接导致组织纤维化和心功能障碍。我们的建议将直接研究成纤维细胞定向募集和单个核纤维化细胞激活的机制，并最终研究这些细胞在驱动大、小血管异常、右心室功能和最终右心室衰竭中的作用。研究将在患者和独特的大型动物疾病模型中进行，这些模型与人类状况非常接近。此外，由于我们已经证明组蛋白修饰参与成纤维细胞表型的表观遗传变化，并且组蛋白去乙酰化酶抑制剂（HDACi）可以关闭激活的成纤维细胞的炎症信号，我们将继续研究，以确定亚型选择性HDAC抑制是否可以通过重编程血管和右心室中表观遗传印迹的促炎成纤维细胞来逆转先前存在的肺动脉高压和心功能障碍。我们的建议包括一个多学科的方法，主要研究人员在临床肺动脉高压，分子心脏病学，

DESCRIPTION (provided by applicant): Right ventricular (RV) failure is by far the most common cause of death in patients with pulmonary arterial hypertension (PAH). At present, little is known of the mechanisms contributing to RV failure in the setting of PAH. It is increasingly appreciated that it is not due simply to distal pulmonary microvascular disease and high pulmonary vascular resistance but rather to complex interactions between the pulmonary circulation and the RV. Inflammation is known to contribute significantly to changes in vascular remodeling in both large and small vessels as well as to RV dysfunction, especially in scleroderma associated PAH (SSc-PAH). Circulating mononuclear-fibrogenic cells have been implicated in inflammation, vascular remodeling, and RV dysfunction by our group and others. We have shown that fibroblasts in PAH patients and in animal models acquire an activated and epigenetically altered phenotype that is capable of generating a microenvironment, which promotes recruitment and activation of circulating mononuclear fibrogenic cells and that these cells contribute directly to tissue fibrosis and cardiac dysfunction. Our proposal will directly examine the mechanisms involved in fibroblast directed recruitment and activation of mononuclear fibrogenic cells and ultimately the role of these cells in driving abnormalities of large and small vessels, RV function and ultimately RV failure. Studies will be conducted in patients and also in unique large animal models of disease that have great fidelity to the human condition. Further, because we have shown that histone modifications are involved in the epigenetic change in fibroblast phenotype and that histone deacetylase inhibitors (HDACi) can turn off inflammatory signaling by activated fibroblasts, we will pursue studies to determine whether isoform selective HDAC inhibition can reverse pre-existing pulmonary hypertension and cardiac dysfunction by reprogramming epigenetically imprinted pro-inflammatory fibroblasts in the vasculature and right ventricle. Our proposal involves a multi- disciplinary approach with Principal Investigators with expertise in clinical pulmonary hypertension, in molecular cardiology, and in cell and molecular biology of fibroblasts and circulating mononuclear cells. Collectively, work by this interdisciplinary group will provide insight into abnormalities of RV-pulmonary arterial interactions in the setting of severe pulmonary hypertension and will lay the groundwork for potential new therapies. PUBLIC HEALTH RELEVANCE: The most common cause of death in patients with pulmonary hypertension is failure of the right side of the heart. Much remains to be learned about why the right heart fails in pulmonary hypertension especially because current therapies are not particularly effective in improving right heart function. We are proposing studies in humans and animals to better understand why the right heart fails and to evaluate the potential for a novel drug therapy beginning with testing in animals.