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: 10630129
• 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/10630129
• 关键词: Acute myocardial infarction; Animal Model; Attenuated; Biopsy Specimen; Blood Vessels; Bone Marrow Transplantation; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cell physiology; Cessation of life; Chronic; Cicatrix; Clinical; 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; MADH2 gene; MAPK8 gene; Macrophage; 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; insight; interstitial; ischemic cardiomyopathy; loss of function; 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 慢性缺血引起的组织纤维化导致多种终末期疾病。这是 众所周知，巨噬细胞在纤维化组织的生成中发挥着重要作用，其中 失调的巨噬细胞积累、激活、极化和功能有助于 基质金属蛋白酶的不受控制的产生和细胞外基质重塑。在下面 在病理条件下，巨噬细胞与成纤维细胞和其他细胞类型一起，充当 TGF-β1 的初始和/或额外来源，并显着促进纤维化。而且， 动脉粥样硬化性冠状动脉疾病患者的心内膜心肌活检标本 缺血性心肌病表现出 45% 的替代性纤维化。因此，识别 巨噬细胞中调节慢性缺血性疾病纤维化的信号级联反应将具有 显着的临床效益。 MKP-5 与先天免疫反应有关， 再生肌生成和血管炎症。我们令人兴奋的初步数据表明 MKP-5 在心脏纤维形成区上调。 MKP-5 的基因删除可以保护 对抗导致冠状动脉供血不足的早期动脉粥样硬化形成，降低心脏功能 纤维化并改善体内缺血引起的心脏功能障碍。体外机制 研究和 RNA-seq 分析表明，MKP-5 的缺失会下调阵列 促纤维化途径基因，包括巨噬细胞和循环中的 TGF-β 信号传导 单核细胞。本研究的中心目标是确定调控的信号级联 巨噬细胞中的 MKP-5 会导致组织纤维化。通过使用一种新型的慢性缺血- 诱导心肌病模型中，我们的目的是：（1）探讨巨噬细胞 MKP-5 在 缺血引起的组织纤维化，（2）揭示巨噬细胞的分子机制 MKP-5 在促纤维化和抗纤维化信号级联的调节中的作用，以及 (3) 测试 新开发的 MKP-5 变构抑制剂抗纤维化的治疗潜力 体内。我们假设 MKP-5 通过巨噬细胞浸润加剧组织纤维化， 极化和 TGF-β 信号传导。拟议研究的成功将确定 MKP-5 的作用 调节慢性缺血引起的组织纤维化；提供申请的概念验证 MKP-5 抑制可用于治疗这种致命疾病。

项目成果

Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype.

• DOI: 10.1152/ajpheart.00594.2022
• 发表时间: 2023-04-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
• 影响因子: 4.8
• 作者: Li, Yijia;Kubo, Hajime;Yu, Daohai;Yang, Yijun;Johnson, Jaslyn P.;Eaton, Deborah M.;Berretta, Remus M.;Foster, Michael;McKinsey, Timothy A.;Yu, Jun;Elrod, John W.;Chen, Xiongwen;Houser, Steven R.
• 通讯作者: Houser, Steven R.

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis.

• DOI: 10.3389/fimmu.2020.595813
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Fu H;Sun Y;Shao Y;Saredy J;Cueto R;Liu L;Drummer C 4th;Johnson C;Xu K;Lu Y;Li X;Meng S;Xue ER;Tan J;Jhala NC;Yu D;Zhou Y;Bayless KJ;Yu J;Rogers TJ;Hu W;Snyder NW;Sun J;Qin X;Jiang X;Wang H;Yang X
• 通讯作者: Yang X

Deletion of LDLRAP1 Induces Atherosclerotic Plaque Formation, Insulin Resistance, and Dysregulated Insulin Response in Adipose Tissue.

LDLRAP1 的缺失会诱导脂肪组织中动脉粥样硬化斑块的形成、胰岛素抵抗和胰岛素反应失调。

• DOI: 10.1016/j.ajpath.2022.03.014
• 发表时间: 2022
• 期刊: The American journal of pathology
• 作者: Leigh,Tani;Kawai,Tatsuo;Preston,Kyle;Kelemen,Sheri;Okune,Rachael;StPaul,Amanda;Corbett,Cali;Peluzzo,AmandaM;Yu,Jun;Scalia,RosarioG;Autieri,MichaelV
• 通讯作者: Autieri,MichaelV

An allosteric site on MKP5 reveals a strategy for small-molecule inhibition.

• DOI: 10.1126/scisignal.aba3043
• 发表时间: 2020-08-25
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Gannam ZTK;Min K;Shillingford SR;Zhang L;Herrington J;Abriola L;Gareiss PC;Pantouris G;Tzouvelekis A;Kaminski N;Zhang X;Yu J;Jamali H;Ellman JA;Lolis E;Anderson KS;Bennett AM
• 通讯作者: Bennett AM

MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis.

• DOI: 10.3389/fimmu.2021.790511
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Zhong C;Min K;Zhao Z;Zhang C;Gao E;Huang Y;Zhang X;Baldini M;Roy R;Yang X;Koch WJ;Bennett AM;Yu J
• 通讯作者: Yu J