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.

器官纤维化可以发生在大多数身体组织中，包括心脏和肺，它是一种严重的 全世界的发病率和死亡率。当组织受损时，它们要么可以正常修复，要么可以 用疤痕修复(在更严重或更长时间的伤害之后)。疤痕组织的形成可能会使人虚弱 当它发生在重要器官，如肺和心脏时，甚至是致命的。遗憾的是，可用的疗法寥寥无几。 治疗心脏和肺纤维化。因此，一个尚未得到满足的主要需求是了解常见的病理过程。 参与推动纤维形成，并开发高效的抗瘢痕治疗方法。这样做的目的是 RFA是从两个或多个器官系统获取信息，以告知我们对共同 研究疾病的发病机制，开发新的治疗方法。 我们的资助申请重点是心脏和肺的疤痕。我们发现了新奇而普通的东西 我们提出的前馈循环会在这些器官和其他器官中推动纤维化。我们的研究团队已经发表了 乳酸脱氢酶A(LDHA)通过增加乳酸的产生而起到肺纤维化的放大作用 酸，可降低局部pH值并激活潜在的转化生长因子β，这是一种强有力的促纤维化细胞因子。分开来看，我们是 首次报道肌钙蛋白相关转录因子A(MRTF-A)促进肌成纤维细胞分化 心脏成纤维细胞。我们现在有了令人兴奋的数据，将这两个观察联系在一起。具体来说，我们有 发现MRTF-A通过LDHA启动子中一个未知的Carg盒驱动LDHA的表达。 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 通过乳酸激活潜伏的转化生长因子β，放大多器官组织纤维化的前馈环 酸乳酸盐产生，以及对该前馈环路的药物抑制代表了一种新的 针对无法治愈的病理反应的治疗策略。我们的具体目标是研究纤维化 肺和心脏的作用机制如下。 具体目的1.研究乳酸/乳酸和乳酸脱氢酶在促进成纤维细胞分化中的作用。 肺和心脏成纤维细胞，并在体内推动肺和心脏纤维化。 具体目的2.研究MRTF-A作为肺和心脏纤维化共同放大因子的作用。 具体目的3.评价新的小分子LDHA抑制剂和mrtf/转化生长因子-β通路的潜力 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机制数据，描述一种新的前馈环路，它放大了 心和肺中的促纤维化信号。我们的发现将显示MRTF-A和LDHA共同作用于 通过乳酸介导的转化生长因子-β的激活促进纤维化。我们还将提供关键的概念验证数据 利用细胞培养和临床前动物模型抑制乳酸代谢途径是一种新的和 肺、心纤维化疾病的有效治疗靶点。