Dysregulation of common metabolic and transcriptional pathways in heart and lung fibrosis

器官纤维化可以发生在大多数身体组织中，包括心脏和肺，并且它是导致心脏病的严重原因。 发病率和死亡率。当组织受损时，它们可以正常修复， 修复疤痕（在更严重或更长时间的损伤后）。疤痕组织的形成会使人衰弱 当它发生在肺和心脏等重要器官时甚至是致命的。可悲的是，几乎没有可用的治疗方法 心脏和肺纤维化因此，一个主要的未满足的需求是了解共同的病理过程 参与驱动纤维化，并开发高效的抗疤痕治疗。的目的 RFA是从两个或多个器官系统中收集信息，以告知我们对常见疾病的理解。 疾病发病机制和开发新的治疗方法。 我们的拨款申请集中在心脏和肺的疤痕。我们发现了新奇而常见的 我们提出的前馈回路驱动了这些和其他器官的纤维化。我们的研究团队发表了 乳酸脱氢酶A（LDHA）通过增加乳酸脱氢酶的产生， 酸，其降低局部pH并激活潜在的TGFβ，一种有效的促纤维化细胞因子。分开来看，我们 第一个报道肌心蛋白相关转录因子A（MRTF-A）驱动肌成纤维细胞分化 心脏成纤维细胞。我们现在有令人兴奋的数据将这两个观察结果联系起来。具体来说，我们有 鉴定了MRTF-A通过LDHA启动子中先前未知的CArG盒驱动LDHA表达。 在这里，我们将检验我们的总体假设，即MRTF-A和LDHA协同作用形成促纤维化蛋白， 前馈回路，通过激活潜伏的TGFβ，通过乳酸 酸-乳酸产生，并且这种前馈回路的药理学抑制代表了一种新的 治疗策略，否则无法治疗的病理反应。我们研究纤维化的具体目标 肺和心脏中的机制如下。 具体目标1。研究乳酸/乳酸盐和LDHA在促进肌成纤维细胞分化中的作用。 肺和心脏成纤维细胞，并在体内驱动肺和心脏纤维化。 具体目标2。研究MRTF-A作为肺和心脏纤维化常见放大器的作用。 具体目标3。评价LDHA和MRTF/TGF-β通路的新型小分子抑制剂作为潜在抑制剂 心脏和肺纤维化的常用治疗药物。 这些研究将提供关键的新的机械数据，描述一种新型的前馈回路， 心脏和肺中的促纤维化信号传导。我们的研究结果将表明，MRTF-A和LDHA共同作用， 通过乳酸介导的TGF-β活化促进纤维化。我们还将提供关键的概念验证数据 使用细胞培养和临床前动物模型，乳酸代谢途径的抑制是一种新的， 肺和心脏纤维化疾病的可行治疗靶点。

Organ fibrosis can occur in most body tissues, including the heart and lung, and it is a serious cause of morbidity and mortality world-wide. When tissues are damaged, they can either repair normally or they can repair with scarring (after a more severe or prolonged injury). The formation of scar tissue can be debilitating and even deadly when it occurs in vital organs such as lung and heart. Sadly, there are few available therapies for cardiac and pulmonary fibrosis. Thus, a major unmet need is to understand common pathologic processes involved in driving fibrogenesis, and to develop highly effective anti-scarring treatments. The objective of this RFA is to garner information from two or more organ systems to inform our understanding of common mechanisms of disease pathogenesis and to develop new therapeutics. Our grant application focuses on cardiac and lung scarring. We have discovered novel and common feedforward loops that we propose drive fibrosis in these and other organs. Our research team has published that Lactate Dehydrogenase A (LDHA) acts as an amplifier of lung fibrosis by increasing production of lactic acid, which lowers the local pH and activates latent TGFβ, a potent pro-fibrotic cytokine. Separately, we were the first to report that Myocardin-Related Transcription Factor A (MRTF-A) drives myofibroblast differentiation of cardiac fibroblasts. We now have exciting data that links these two observations. Specifically, we have identified that MRTF-A drives LDHA expression via a previously unknown CArG box in the LDHA promoter. Here, we will test our overall hypothesis that MRTF-A and LDHA act in concert to form a pro-fibrotic feed-forward loop that amplifies tissue fibrosis in multiple organs by activating latent TGFβ, via lactic acid-lactate production, and that pharmacologic inhibition of this feed-forward loop represents a novel therapeutic strategy for an otherwise untreatable pathologic response. Our Specific Aims to study fibrotic mechanisms in lung and heart are as follows. Specific Aim 1. Investigate the role of lactic acid/lactate and LDHA in promoting myofibroblast differentiation of lung and cardiac fibroblasts, and in driving pulmonary and cardiac fibrosis in vivo. Specific Aim 2. Investigate the role of MRTF-A as a common amplifier of fibrosis in lung and heart. Specific Aim 3. Evaluate novel small molecule inhibitors of LDHA and the MRTF/TGF-β pathway as potential common therapeutic agents for cardiac and lung fibrosis. These studies will provide key new mechanistic data describing a novel feed-forward loop that amplifies pro-fibrotic signaling in both heart and lung. Our findings will show that MRTF-A and LDHA act together to promote fibrosis via lactic acid-mediated activation of TGF-β. We will also provide critical proof-of concept data using cell culture and preclinical animal models that inhibition of the lactate metabolic pathway is a novel and viable therapeutic target in fibrosing diseases of lung and heart.