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: 10034005
• 负责人: Jun Yu
• 金额: $ 53.91万
• 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/10034005
• 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.

抽象的 慢性缺血诱导的组织纤维化有助于多种末期疾病。这是 公认的巨噬细胞在纤维化组织的产生中起着重要作用 失调的巨噬细胞积累，激活，极化和功能有助于 基质金属蛋白酶和细胞外基质重塑的不受控制的产生。在下面 病理状况，巨噬细胞以及成纤维细胞和其他细胞类型 TGF-β1的初始和/或其他来源，并显着有助于纤维化。而且， 来自动脉粥样硬化冠状动脉疾病诱导的患者的心内膜活检标本 缺血性心肌病显示45％的替代纤维化。那，确定 巨噬细胞中调节慢性缺血性疾病纤维化的巨噬细胞的信号传导级联 重大临床益处。 MKP-5在先天免疫反应中隐含 再生肌发生和血管感染。我们令人兴奋的初步数据表明 MKP-5在心脏的纤维化区域进行了更新。 MKP-5的遗传缺失保护 反对导致冠状动脉功能不全的早期动脉粥样硬化发生，会下降心脏 纤维化和缓解体内缺血诱导的心脏功能障碍。体外机械 研究和RNA-seq分析表明，MKP-5下调的损失 纤维化途径基因包括巨噬细胞中的TGF-β信号传导和循环 单核细胞。这项研究的核心目标是确定受调节的信号级联 通过MKP-5在巨噬细胞中导致组织纤维化。通过使用新型的慢性缺血 - 诱导心肌病模型，我们的目标是：（1）质疑巨噬细胞MKP-5在 缺血诱导的组织纤维化，（2）发现巨噬细胞的分子机制 MKP-5在调节促纤维化信号传导级联方面，（3）测试 新开发的MKP-5变构抑制剂对纤维化的治疗潜力 体内。我们假设MKP-5通过巨噬细胞浸润加剧了组织纤维化， 极化和TGF-β信号传导。拟议研究的成功将定义MKP-5的作用 调节慢性缺血诱导的组织纤维化；提供申请证明证明 MKP-5抑制这种致命疾病。