Ectonucleotidases in ischemic heart disease

外切核苷酸酶在缺血性心脏病中的作用

基本信息

批准号：
9922592
负责人：
Richard J Gumina
金额：
$ 37.91万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-14 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9922592
关键词：
Acute myocardial infarction Address Adenosine Adenosine Monophosphate Anti-inflammatory Attenuated Bone Marrow Cardiac Cardiovascular Diseases Cardiovascular Pathology Cells Cicatrix Data Enzymes Equilibrium Extracellular Matrix Fibroblasts Fibrosis Funding Goals Heart Heart Diseases Heart failure Hydrolysis Image In Vitro Inflammation Inflammatory Inflammatory Response Integral Membrane Protein Interleukin-4 Kidney Knock-out Lead Liver Lung Mass Spectrum Analysis Measurable Mediating Mediator of activation protein Metabolic Pathway Molecular Myocardial Infarction Myocardial Ischemia Myocardial rupture Nucleotides Outcome Study P2X-receptor Pathway interactions Patients Phenotype Process Purinergic P1 Receptors Purinergic P2 Receptors Purinoceptor Receptor Activation Reperfusion Injury Role STEM research Signal Pathway Signal Transduction Skin Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Testing Thrombosis United States Up-Regulation Work autocrine base biosignature cardiac repair coronary fibrosis extracellular healing in vivo macrophage myocardial damage novel novel therapeutic intervention novel therapeutics paracrine prevent repaired response restraint translational impact tripolyphosphate

项目摘要

More than 1 million people in the United States suffer a myocardial infarction (MI) each year. Myocardial infarction (MI) evokes an intense inflammatory response. Paracrine and autocrine released extracellular ATP (eATP), signaling through purinergic P2 receptors (P2X and P2Y), is a potent modulator of macrophage and fibroblast function. Extracellular ATP is hydrolyzed by the transmembrane protein Ectonucleoside triphosphate diphosphohydrolase 1 (CD39) to yield adenosine monophosphate (AMP), thereby halting pro-inflammatory ATP-mediated signaling. This goal of the project is to define the role of the macrophage and fibroblast- expressed CD39 on post-MI cardiac repair. To accomplish this goal we propose the following: Aim 1: To determine whether CD39 up-regulation is a protective mechanism that constrains autocrine ATP-driven inflammation, preventing exaggerated macrophage responses, and protecting from adverse post-MI fibrosis we will: 1) determine how CD39 activity impacts TLR-4-dependent and IL-4-dependent macrophage functions in vitro, 2) determine the impact of CD39 activity on the in vivo macrophage phenotypic transition from inflammatory to profibrotic functions during post-MI repair, and 3) Determine the role of macrophage CD39 on post-MI repair fibrosis in vivo. Aim 2: To dissect the purinergic pathways involved in CD39-mediated restraint of TGF-β1 activation of cardiac fibroblasts and determine the role of CD39 upregulation in modulating fibroblast function and regulating cardiac repair following MI we will 1) determine the downstream targets through which CD39 attenuates TGF-β1-mediated cardiac fibroblast inflammatory and fibrotic responses, 2) determine the impact of CD39 on the in vivo cardiac fibroblast phenotype during cardiac repair and 3) determine the impact of fibroblast CD39 on in vivo extracellular matrix remodeling during post-MI repair. Secondary Aim: To determine the impact of CD39 expression extracellular matrix remodeling we will use state-of-the-art MALDI-imaging mass spectroscopy to define the early and late biosignatures of cardiac ECM remodeling post-MI and determine the impact of CD39 on ECM remodeling. The outcomes of these studies will reveal the fundamental pathways by which CD39 regulates post-MI myocardial repair and could allow novel therapeutic approaches not only to treat fibrotic disorders of the heart, but also of the skin, lungs, bone marrow, liver, or kidneys, thereby providing an important translational impact.

美国每年有超过 100 万人患有心肌梗塞 (MI)。梗塞 (MI) 会引起强烈的炎症反应，旁分泌和自分泌释放细胞外 ATP。 (eATP) 通过嘌呤能 P2 受体（P2X 和 P2Y）发出信号，是巨噬细胞和细胞外 ATP 被跨膜蛋白外核苷三磷酸水解。二磷酸水解酶 1 (CD39) 产生单磷酸腺苷 (AMP)，从而阻止促炎该项目的目标是确定巨噬细胞和成纤维细胞的作用。在 MI 后心脏修复中表达 CD39 为了实现这一目标，我们提出以下建议：目标 1：确定 CD39 上调是否是一种限制自分泌 ATP 驱动的保护机制炎症，防止巨噬细胞过度反应，并防止不良的心肌梗死后纤维化将：1) 确定 CD39 活性如何影响 TLR-4 依赖性和 IL-4 依赖性巨噬细胞功能体外，2)确定CD39活性对体内巨噬细胞表型转变的影响 MI 后修复过程中炎症至促纤维化功能的变化，以及 3) 确定巨噬细胞 CD39 对纤维化功能的作用目的 2：剖析参与 CD39 介导的抑制的嘌呤能途径。 TGF-β1 激活心脏成纤维细胞并确定 CD39 上调在调节成纤维细胞中的作用 MI 后的功能和调节心脏修复，我们将 1) 确定下游目标，通过这些目标 CD39 减弱 TGF-β1 介导的心脏成纤维细胞炎症和纤维化反应，2) 确定心脏修复过程中 CD39 对体内心脏成纤维细胞表型的影响，3) 确定成纤维细胞 CD39 对 MI 后修复期间体内细胞外基质重塑的影响。 CD39 表达对细胞外基质重塑的影响我们将使用最先进的 MALDI 成像质谱来定义 MI 后心脏 ECM 重塑的早期和晚期生物特征确定 CD39 对 ECM 重塑的影响这些研究的结果将揭示基本原理。 CD39 调节 MI 后心肌修复的途径并可能带来新的治疗方法不仅可以治疗心脏的纤维化疾病，还可以治疗皮肤、肺、骨髓、肝脏或肾脏的纤维化疾病，从而提供重要的转化影响。