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

心肺纤维化常见代谢和转录途径的失调

• 批准号: 9170621
• 负责人: RICHARD P. PHIPPS
• 金额: $ 53.73万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9170621
• 关键词: Amplifiers; Animal Model; Applications Grants; Automobile Driving; Binding Sites; Boxing; CRISPR/Cas technology; Cardiac; Cause of Death; Cell Culture Techniques; Cicatrix; Clinical; Coculture Techniques; Data; Differentiation Antigens; Disease; Extracellular Matrix; Fibroblasts; Fibrosis; Genes; Health; Heart; Human; In Vitro; Injury; Knock-out; Lactic acid; Link; Lung; Lung diseases; Mediating; Metabolic; Metabolic Pathway; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Organ; Pathogenesis; Pathologic; Pathologic Processes; Pathway interactions; Phenotype; Production; Publishing; Pulmonary Fibrosis; Regulatory Pathway; Reporting; Research; Role; Signal Transduction; Structure of parenchyma of lung; System; Testing; Therapeutic; Therapeutic Agents; Tissues; Transforming Growth Factor beta; Transgenic Mice; Up-Regulation; Wound Healing; body system; coronary fibrosis; cytokine; design; factor A; feeding; fibrogenesis; in vivo; inhibitor/antagonist; lactate dehydrogenase A; mortality; mouse model; myocardin; novel; novel therapeutics; overexpression; pre-clinical; preclinical study; prevent; promoter; repaired; response; small molecule inhibitor; stem; therapeutic target; transcription factor

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.

器官纤维化可能在大多数身体组织中发生，包括心脏和肺，这是严重的原因 全球发病率和死亡率。当组织损坏时，它们可以正常修理，也可以 用疤痕修复（严重或长时间受伤后）。疤痕组织的形成可能使人衰弱 甚至是致命发生在肺和心脏等重要器官中时。可悲的是，几乎没有可用的疗法 用于心脏和肺纤维化。这是一个主要的未满足需要是了解常见的病理过程 参与驱动纤维发生，并开发高效的抗囊治疗方法。这个目的 RFA将从两个或多个器官系统中获得信息，以告知我们对常见的理解 疾病发病机理和发展新疗法的机制。 我们的赠款申请专注于心脏和肺部疤痕。我们发现了小说和常见 我们建议在这些和其他器官中驱动纤维化的前馈回路。我们的研究团队已发表 乳酸脱氢酶A（LDHA）通过增加乳酸产生而充当肺纤维化的放大器 酸会降低局部pH并激活潜在的促纤维性细胞因子。单独，我们是 第一个报告与心肌相关的转录因子A（MRTF-A）驱动肌成纤维细胞的分化 心脏成纤维细胞。现在，我们有令人兴奋的数据将这两个观察结果链接起来。具体来说，我们有 确定MRTF-A通过LDHA启动子中以前未知的Carg盒子驱动LDHA表达。 在这里，我们将测试MRTF-A和LDHA协同作用以形成促纤维化的整体假设 通过乳酸激活潜在的TGFβ，可以通过乳酸激活多个器官中的组织纤维化。 酸乳酸的产生，并且该进料前环的药物抑制代表了一种新颖的 原本不可治疗的病理反应的治疗策略。我们研究纤维化的具体目的 肺和心脏的机制如下。 具体目标1。研究乳酸/乳酸和LDHA在促进肌纤维细胞分化中的作用 肺和心脏成纤维细胞，以及在体内驱动肺和心脏纤维化时。 具体目标2。研究MRTF-A作为肺和心脏纤维化的常见放大器的作用。 特定目的3。评估LDHA和MRTF/TGF-β途径的新型小分子抑制剂 心脏和肺纤维化的常见治疗剂。 这些研究将提供关键的新机械数据，描述一个新型的进料回路，以放大器 心脏和肺中的促纤维性信号传导。我们的发现将表明MRTF-A和LDHA一起行动 通过乳酸介导的TGF-β激活促进纤维化。我们还将提供关键的概念验证数据 使用抑制鞋底代谢途径的细胞培养和临床前动物模型是一种新颖， 可行的治疗靶标在肺和心脏的纤维疾病中。