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：
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
项目类别：
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&apos -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

项目摘要

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。该申请要求有前途的多元化候选人有机会扩展他的领域调查提出了一个关于 CD39 活性在心血管疾病中的作用的新问题。一、研究计划我们目前的 R01 R01HL127442，外核苷酸酶在缺血性心脏病中的作用，研究 CD39 的影响巨噬细胞和成纤维细胞对心肌梗塞后愈合的活性（参见家长的具体目标以下为斜体字）。将提供新颖的培训机会，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，新方向将检验 CD39 对单核细胞的假设。影响细胞表型，可作为炎症的预后标志物和潜在的治疗方法心血管疾病的新治疗目标。家长补助金的具体目标（摘自 R01）：具体目标：美国每年有超过 100 万人患有急性心肌梗死 (MI) 最佳的心脏修复需要控制炎症和纤维化反应。心脏愈合可能导致致命的心脏破裂；异常纤维化可能导致衰弱性心力衰竭。目前针对心脏修复的治疗方法是有限的，迫切需要了解新的治疗方法。调节心脏修复的途径并开发预防心力衰竭的新疗法。急性心肌梗死导致死亡细胞最初释放核苷酸。激活炎症细胞和成纤维细胞同样重要，可以激活细胞外ATP（eATP）。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受体信号通路（P2X 和 P2Y）产生促炎和促纤维化介质。 eATP 水解为腺苷是通过核酸外切酶 CD39 和 CD73 据称具有抗炎和抗纤维化作用。通过 P1 嘌呤能受体激活进行反应因此，CD39/CD73 途径是一个重要的途径。平衡炎症和纤维化的调节尺度是这种代谢的限速步骤。因此，我们之前的研究重点是了解它对心血管病理学的影响。 R21 资助的工作剖析了增加 CD39 活性的分子和细胞途径减少缺血再灌注损伤后的动脉血栓形成和心肌损伤。我们的长期目标是了解核酸外切酶活性对心血管疾病的作用。 CD39 活性对调节 MI 后心脏修复的影响尚不清楚。该应用的目的是了解 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调节 CD39 的细胞特异性表达。对于解决 MI 后的炎症和纤维化反应是必要的。源于我们的初步数据，该数据表明 CD39 活性的敲除会导致心脏恶化为了确定导致这一发现的下游靶点，我们重点关注了 CD39 对巨噬细胞和心脏成纤维细胞的作用部分基于我们的初步数据。展示巨噬细胞和心脏上 CD39 表达和活性的动态变化成纤维细胞，我们渴望巨噬细胞和成纤维细胞上 CD39 的上调，作为分子灭火器，终止促进炎症的核苷酸介导的嘌呤能信号为了检验我们的假设，我们将探索不同但相关的目标。目标 1：确定 CD39 上调是否是一种限制自分泌的保护机制 ATP 驱动的炎症，防止巨噬细胞过度反应，并防止不良反应心肌梗死后纤维化。目标 2：剖析参与 CD39 介导的抑制 TGF-β1 激活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中的作用调节 MI 后的心脏修复。次要目标：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，并可能允许新的治疗方法不仅可以治疗心肌纤维化疾病心脏，而且还包括皮肤、肺、骨髓、肝脏或肾脏，从而提供重要的翻译影响。