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。 此应用程序请求有希望的多样性候选人有机会扩展他的领域 调查采取了一个关于CD39活性在心血管疾病中的作用的新问题。 1.研究计划 我们目前的R01 R01HL127442，在缺血性心脏病中的胞外核苷酸酶，研究CD39的影响 巨噬细胞和成纤维细胞在心肌梗死后愈合中的活性(见Parent的具体目标 以斜体字表示的赠款)。此申请是为罗曼·科瓦鲁比亚博士提供的多样性培训补充资料 将提供一个新的培训机会，同时扩展CD39作用的基础研究 在单核细胞和巨噬细胞生物学中。新的方向将检验单核细胞上CD39的假设 影响细胞表型，可作为炎症的预后标志和潜在的治疗方法 心血管疾病新疗法的目标。 Parent Grant特定目标(摘自R01)： 具体目标：美国每年有100多万人患有急性心肌梗死(MI) 各州。最佳的心脏修复需要控制炎症和纤维化反应。不足之处 心脏愈合可导致致命的心脏破裂；反常的纤维化可导致衰弱的心力衰竭。 目前针对心脏修复的治疗是有限的。理解小说是非常必要的。 调节心脏修复和开发预防心力衰竭的新疗法的途径。 急性心肌梗塞导致死亡细胞最初释放核苷酸。然而，通过以下方式释放核苷酸 活化的炎症细胞和成纤维细胞同样重要。胞外三磷酸腺苷(EATP)可以激活 巨噬细胞(M？S)和心脏成纤维细胞(CFs)旁分泌和自分泌的嘌呤能 产生促炎和促纤维化介质的受体信号通路(P2X和P2Y)。这个 EATP的水解为腺苷是通过下列顺序的作用完成的： 胞外核苷酸酶CD39和CD73。据说腺苷具有抗炎和抗肝纤维化的作用。 通过激活P1嘌呤能受体的反应。因此，CD39/CD73通路是一个重要的 平衡炎症和纤维化的监管规模。CD39是这种代谢的限速步骤 因此，我们一直专注于了解它对心血管病理的影响。我们的前辈 R21资助的研究剖析了CD39活性增加的分子和细胞途径 减少动脉血栓形成和缺血再灌注损伤后的心肌损伤。 我们的长期目标是了解ECN活性在心血管疾病中的作用。这个 CD39活性在调节心肌梗死后心脏修复中的作用尚不清楚。因此，目标是 这一应用的目的是了解CD39活性的细胞和分子机制 调节心肌梗塞后的修复和纤维化。我们的假设是，受调控的CD39的细胞特异性表达 是解决心肌梗死后炎症和纤维化反应所必需的。这项研究的基本原理 源于我们的初步数据表明，CD39活性的敲除加剧了心脏 心肌梗死后纤维化。为了确定对这一发现负责的下游目标，我们将重点放在 CD39在巨噬细胞和心脏成纤维细胞中的作用。部分基于我们的初步数据 显示巨噬细胞和心脏CD39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，作为一种 分子灭火器，终止促进炎症的核苷酸介导的嘌呤能信号 以及梗死心脏的纤维化。为了检验我们的假设，我们将探索不同但相关的目标。 目的1：确定CD39上调是否是抑制自分泌的保护性机制 ATP驱动的炎症，防止夸大的巨噬细胞反应，保护免受不良影响 心肌梗塞后纤维化。 目的2：分析CD39抑制转化生长因子-β-1活化的嘌呤能途径。 并确定CD39上调在调节成纤维细胞功能中的作用 调节心肌梗死后的心脏修复。 第二目的：探讨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调节心肌梗死后的基本途径 心肌修复，并可能使新的治疗方法不仅可以治疗纤维化的疾病 心脏，也包括皮肤、肺、骨髓、肝脏或肾脏，从而提供重要的 翻译影响。