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背景下导致RV衰竭的机制知之甚少。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RV之间的复杂相互作用。已知炎症可显著促进大血管和小血管中血管重塑的变化以及RV功能障碍，尤其是在硬皮病相关PAH（SSc-PAH）中。循环单核纤维化细胞与炎症、血管重塑和RV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活化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活化，这些细胞直接导致组织纤维化和心功能障碍。我们的提案将直接研究成纤维细胞定向募集和单核纤维化细胞活化的机制，并最终研究这些细胞在驱动大小血管异常、RV功能和最终RV衰竭中的作用。研究将在患者和独特的大型疾病动物模型中进行，这些模型对人类状况有很大的保真度。此外，因为我们已经表明组蛋白修饰参与成纤维细胞表型的表观遗传变化，并且组蛋白脱乙酰酶抑制剂（HDACi）可以关闭激活的成纤维细胞的炎症信号传导，我们将继续研究，以确定是否异构体选择性HDAC抑制可以逆转预先存在的肺动脉高压和心功能不全，通过重编程表观遗传印记的前，血管系统和右心室中的炎性成纤维细胞。我们的建议涉及多学科的方法，主要研究者在临床肺动脉高压，分子心脏病学， 以及成纤维细胞和循环单核细胞的细胞和分子生物学。总的来说，这个跨学科小组的工作将提供对严重肺动脉高压背景下RV-肺动脉相互作用异常的深入了解，并为潜在的新疗法奠定基础。

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.