Ectonucleotidases in ischemic heart disease

外切核苷酸酶在缺血性心脏病中的作用

• 批准号: 10025031
• 负责人: Richard J Gumina
• 金额: $ 5.36万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10025031
• 关键词: 5' -Nucleotidase; Acute myocardial infarction; Adenosine; Affect; Algorithms; Anti-Inflammatory Agents; B-Lymphocytes; Biology; Blood Vessels; Bone Marrow; CD14 gene; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Carotid Artery Thrombosis; Cell Separation; Cells; Chronic; Cicatrix; Data; Deposition; Development; Dimensions; Disease; Doctor of Philosophy; Enzymes; Equilibrium; Exposure to; Extracellular Matrix; FCGR3B gene; Fibroblasts; Fibrosis; Funding; Goals; Heart; Heart Diseases; Heart failure; Homeostasis; Human; Hydrolysis; Hyperactive behavior; IACUC; Immune; Immune system; Inflammation; Inflammatory; Institutional Review Boards; Investigation; Italy; Kidney; Knock-out; Lead; Lipids; Liver; Lung; Maintenance; Measures; Mediating; Mediator of activation protein; Metabolic Pathway; Molecular; Mus; Mutation; Myelogenous; Myocardial Infarction; Myocardial Ischemia; Myocardial rupture; Nucleotides; Outcome Study; P2X-receptor; Parents; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Play; Population; Population Heterogeneity; Predictive Value; Process; Prognostic Marker; Purinergic P1 Receptors; Purinoceptor; Receptor Activation; Reperfusion Injury; Request for Applications; Research; Role; STEM research; Signal Pathway; Signal Transduction; Skin; Surface; Testing; Therapeutic; Thrombosis; Training; United States; Up-Regulation; Variant; Work; autocrine; base; cardiac repair; coronary fibrosis; extracellular; genetic variant; healing; healthy volunteer; inflammatory marker; innovation; macrophage; monocyte; mouse model; myocardial damage; neutrophil; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; paracrine; parent grant; phenome; prevent; repaired; response; restraint; therapy outcome; training opportunity; translational impact; tripolyphosphate; young adult

Abstract. This application requests an opportunity for a promising diversity candidate to expand his field of investigation to take on a new question regarding the role of CD39 activity in cardiovascular disease. 1. Research Plan Our current R01 R01HL127442, Ectonucleotidases in ischemic heart disease, studies the impact of CD39 activity on macrophages and fibroblast on post-myocardial infarction healing (see specific aims of parent grant in italics below). This application for a Diversity Training Supplement for Roman Covarrubias, PhD will provide a novel training opportunity while expanding upon the fundamental studies of the role of CD39 in monocyte and macrophage biology. The new direction will test the hypothesis that CD39 on monocytes impacts cell phenotype and may serve both as a prognostic marker of inflammation and a potential therapeutic target for novel treatment of cardiovascular disease. Parent Grant Specific Aims (extracted from R01): SPECIFIC AIMS: Over 1 million people per year suffer an acute myocardial infarction (MI) in the United States. Optimal cardiac repair requires controlled inflammatory and fibrotic responses. Inadequate cardiac healing can result in fatal cardiac rupture; aberrant fibrosis can lead to debilitating heart failure. Current treatments that target cardiac repair are limited. There is a critical need to understand novel pathways that modulate cardiac repair and to develop new therapies to prevent heart failure. Acute MI results in an initial release of nucleotides by dying cells. However, nucleotide release by activated inflammatory cells and fibroblasts is equally important. Extracellular ATP (eATP) can activate macrophages (MØs) and cardiac fibroblasts (CFs) through both paracrine and autocrine purinergic receptor signaling pathways (P2X and P2Y) to produce proinflammatory and profibrotic mediators. The hydrolysis of eATP to adenosine is accomplished through the sequential actions of the ectonucleotidases CD39 and CD73. Adenosine is purported to evoke anti-inflammatory and anti-fibrotic responses via P1 purinergic receptor activation. Therefore, the CD39/CD73 pathway is an important regulatory scale that balances inflammation and fibrosis. CD39 is the rate-limiting step in this metabolic pathway, as such, we have focused on understanding it's impact on cardiovascular pathology. Our prior R21 funded work dissected the molecular and cellular pathways by which increased CD39 activity reduces arterial thrombosis and myocardial damage following ischemia-reperfusion injury. Our long-term goal is to understand the role of ectonucleotidase activity on cardiovascular disease. The impact of CD39 activity on regulating cardiac repair after MI is not known. Therefore, the objective of this application is to understand the cellular and molecular mechanisms by which CD39 activity modulates post-MI repair and fibrosis. Our hypothesis is that regulated cell-specific expression of CD39 is necessary to resolve the inflammatory and fibrotic responses post-MI. The rationale for this research stems from our preliminary data that demonstrate that knockout of CD39 activity exacerbates cardiac fibrosis post-MI. To determine downstream targets responsible for this finding, we have focused on the role CD39 on macrophages and cardiac fibroblasts. Based, in part, on our preliminary data demonstrating dynamic changes in the expression and activity of CD39 on macrophages and cardiac fibroblasts, we hypothesize that upregulation of CD39 on macrophages and fibroblasts, serves as a molecular extinguisher, terminating nucleotide-mediated purinergic signals that promote inflammation and fibrosis in the infarcted heart. To test our hypothesis, we will explore distinct but related aims. 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. 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. Secondary Aim: To determine the impact of CD39 expression on extracellular matrix 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.

抽象的。 该申请要求有机会让承诺多样性候选人扩大其领域 调查要提出有关CD39活性在心血管疾病中的作用的新问题。 1。研究计划 我们当前的R01 R01HL127442，缺血性心脏病中的卵母肠差，研究CD39的影响 对巨噬细胞和成纤维细胞的活性在心肌梗死后愈合（请参阅父母的特定目的） 以下授予斜体）。该申请为罗马Covarrubias博士提供多样性培训补充 将提供一个新颖的培训机会，同时扩展CD39角色的基本研究 在单核细胞和巨噬细胞生物学中。新方向将测试单核细胞上CD39的假设 影响细胞表型，并且可以用作感染的预后标志，又可能是潜在疗法 对心血管疾病的新型治疗的靶标。 父授予特定的目标（摘自R01）： 具体目标：每年超过100万人患者急性心肌梗塞（MI） 国家。最佳心脏修复需要受控的炎症和纤维化反应。不足 心脏愈合会导致致命的心脏破裂；异常纤维化会导致心力衰竭使人衰弱。 靶向心脏修复的当前治疗方法受到限制。有迫切需要理解小说 调节心脏修复并开发新疗法以防止心力衰竭的途径。 急性MI导致垂死细胞最初释放核苷酸。但是，核苷酸释放 活化的炎症细胞和成纤维细胞同样重要。细胞外ATP（EATP）可以激活 巨噬细胞（Møs）和心脏成纤维细胞（CFS）通过旁分泌和自分泌嘌呤能 接收器信号通路（P2X和P2Y）可产生促炎和纤维化介体。这 EATP水解为腺苷是通过顺序作用完成的 核苷酸酶CD39和CD73。腺苷据称可以引起抗炎和抗纤维化 通过P1嘌呤能受体激活的反应。因此，CD39/CD73途径是重要的 平衡注射和纤维化的调节量表。 CD39是这种代谢的限制步骤 因此，我们专注于理解它对心血管病理的影响。我们的先验 R21资助的工作解剖了CD39活性增加的分子和细胞途径 缺血 - 再灌注损伤后，减少动脉血栓形成和心肌损伤。 我们的长期目标是了解依顿核苷酸酶活性在心血管疾病中的作用。这 尚不清楚CD39活性对MI后控制心脏修复的影响。因此，目标 该应用的是了解CD39活性的细胞和分子机制 调节MI后修复和纤维化。我们的假设是CD39调节的细胞特异性表达 在MI后解决炎症和纤维化反应是必要的。这项研究的理由 源自我们的初步数据，这些数据表明CD39活性的敲除加剧心脏 纤维化后。为了确定负责这一发现的下游目标，我们专注于 巨噬细胞和心脏成纤维细胞的角色CD39。部分基于我们的初步数据 证明CD39对巨噬细胞和心脏的表达和活性的动态变化 成纤维细胞，我们假设CD39在巨噬细胞和成纤维细胞上上调 分子灭火器，终止核介导的嘌呤能信号，促进注射 和梗塞心脏的纤维化。为了检验我们的假设，我们将探讨不同但相关的目标。 目的1：确定CD39上调是否是受保护自分泌的受保护机制 ATP驱动的炎症，防止夸张的巨噬细胞反应并保护对抗 MI后纤维化。 目标2：剖析与CD39介导的TGF-β1激活的CD39介导的约束的嘌呤能途径 心脏成纤维细胞并确定CD39上调在调节成纤维细胞功能和 MI后调节心脏修复。 次要目的：确定CD39表达对细胞外基质重塑的影响。 这些研究的结果将揭示CD39调节MI后的基本途径 心肌修复，可以允许新型治疗方法不仅可以治疗纤维化疾病 心脏，也是皮肤，肺，骨髓，肝或肾脏，从而提供重要的 翻译影响。