Molecular control of ischemia-induced tissue fibrosis

缺血引起的组织纤维化的分子控制

• 批准号: 10171906
• 负责人: Jun Yu
• 金额: $ 52.45万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171906
• 关键词: Acute myocardial infarction; Animal Model; Attenuated; Biopsy Specimen; Bone Marrow Transplantation; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cell physiology; Cessation of life; Chronic; Cicatrix; Clinical; Consequentialism; Coronary Arteriosclerosis; Coronary artery; Data; Development; Disease; Drug Targeting; Event; Exhibits; Extracellular Matrix; Failure; Fibroblasts; Fibrosis; Functional disorder; Gene Expression; Generations; Genes; Genetic; Goals; Grant; Heart; Heart Atrium; Heart Diseases; Human; Human Pathology; Immune; Impairment; In Vitro; Individual; Infiltration; Inflammatory; Injury; Innate Immune Response; Interleukin-10; Ischemia; Knockout Mice; Lead; MADH2 gene; MAP Kinase Gene; MAPK8 gene; Matrix Metalloproteinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Muscle; Myocardial Infarction; Myocardial dysfunction; Organ; Pathologic; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Pre-Clinical Model; Production; Regulation; Research; Research Support; Role; Sampling; Signal Transduction; Source; Specificity; T-Lymphocyte; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Vascular blood supply; atherogenesis; cell type; coronary artery occlusion; coronary fibrosis; cytokine; end stage disease; gain of function; heart function; heart preservation; idiopathic pulmonary fibrosis; in vivo; in vivo Model; inhibitor/antagonist; insight; interstitial; ischemic cardiomyopathy; macrophage; monocyte; mortality; mouse model; myogenesis; new therapeutic target; novel; osteopontin; p38 Mitogen Activated Protein Kinase; prevent; protective effect; regenerative; small molecule; success; therapeutic evaluation; transcriptome sequencing; vascular inflammation

Abstract Chronic ischemia induced tissue fibrosis contributes to numerous end-stage diseases. It is well accepted that macrophages play a major role in the generation of fibrotic tissues whereby dysregulated macrophage accumulation, activation, polarization and functions contribute to uncontrolled production of matrix metalloproteinases and extracellular matrix remodeling. Under pathological conditions, macrophages, along with fibroblasts and other cell types, serve as an initial and/or additional source of TGF-β1 and significantly contribute to the fibrosis. Moreover, endomyocardial biopsy specimens from patients with atherosclerotic coronary disease-induced ischemic cardiomyopathy demonstrated 45% of replacement fibrosis. Thus, identifying the signaling cascades in macrophage that regulates fibrosis in chronic ischemic diseases will have significant clinical benefit. MKP-5 has been implicated in innate immune responses, regenerative myogenesis and vascular inflammation. Our exciting preliminary data show that MKP-5 is upregulated in the fibrogenic zone of the heart. Genetic deletion of MKP-5 protects against early atherogenesis that leads to coronary artery insufficiency, decreases cardiac fibrosis and ameliorates ischemia-induced cardiac dysfunction in vivo. In vitro mechanistic studies and RNA-seq analysis suggested that loss of MKP-5 downregulated arrays of profibrogenic pathway genes including TGF-β signaling in macrophages and circulating monocytes. The central goal of this study is to identify the signaling cascades regulated by MKP-5 in macrophage that lead to tissue fibrosis. By using a novel chronic ischemia- induced cardiomyopathy model, we aim to: (1) interrogate the role of macrophage MKP-5 in ischemia-induced tissue fibrosis, (2) uncover the molecular mechanisms of macrophage MKP-5 in regulation of pro- and anti-fibrogenic signaling cascade, and (3) test the therapeutic potential of a newly developed MKP-5 allosteric inhibitor against fibrosis in vivo. We hypothesize that MKP-5 exacerbates tissue fibrosis through macrophage infiltration, polarization and TGF-β signaling. The success of proposed study will define the role of MKP-5 in regulating chronic ischemia-induced tissue fibrosis; provide proof-of-concept for applying MKP-5 inhibition for the management of this deadly disease.

摘要 慢性缺血引起的组织纤维化可导致多种终末期疾病。它是 众所周知，巨噬细胞在纤维组织的形成中发挥着重要作用， 巨噬细胞聚集、激活、极化和功能失调导致 无节制地产生基质金属蛋白酶和细胞外基质重塑。在……下面 病理条件下，巨噬细胞与成纤维细胞和其他类型的细胞一起，作为 转化生长因子-β-1的初始和/或额外来源，并显著促进纤维化。此外， 动脉粥样硬化性冠心病患者的心内膜心肌活检标本 缺血性心肌病表现为45%的替代性纤维化。因此，标识 调节慢性缺血性疾病纤维化的巨噬细胞中的信号级联将 显著的临床益处。MKP-5与先天免疫反应有关， 再生性肌肉生成和血管炎症。我们令人振奋的初步数据显示 MKP-5在心脏纤维化区表达上调。MKP-5基因缺失保护 抗早期动脉粥样硬化，导致冠状动脉功能不全，降低心脏 肝纤维化和改善体内缺血所致的心功能障碍。体外机制 研究和RNA-SEQ分析表明，MKP-5基因的缺失下调了 包括转化生长因子-β信号在内的促纤维化通路基因在巨噬细胞和循环中的表达 单核细胞。这项研究的中心目标是确定受调控的信号级联 通过巨噬细胞中的MKP-5导致组织纤维化。通过使用一种新的慢性缺血- 我们的目的是：(1)探讨巨噬细胞MKP-5在心肌病中的作用。 缺血诱导组织纤维化，(2)揭示巨噬细胞的分子机制 MKP-5在调节促纤维化和抗纤维化信号级联中的作用，以及(3)检测 新开发的MKP-5变构抑制剂抗肝纤维化的作用 活着。我们假设MKP-5通过巨噬细胞的渗透而加剧组织纤维化， 极化和转化生长因子-β信号转导。拟议研究的成功将确定MKP-5的作用 在调节慢性缺血诱导的组织纤维化方面；为应用提供概念验证 MKP-5抑制剂用于治疗这一致命疾病。