The role of GATA3-positive macrophages in cardiovascular pathologies

GATA3 阳性巨噬细胞在心血管病理中的作用

基本信息

批准号：
10643888
负责人：
Prediman Krishan Shah
金额：
$ 41.75万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643888
关键词：
Acute myocardial infarction Affect Agonist Area Arterial Fatty Streak Arterial Injury Atherosclerosis Attenuated Biological Markers Bone Marrow Transplantation Cardiac Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Caring Cell Culture Techniques Cells Cholesterol Clinical Clinical Trials Complication Cost Measures Data Developing Countries Development Disease Disease Progression Economic Burden Environment Event Experimental Models Future GATA3 gene Genetic Transcription Goals Heart Heart Diseases Heart failure Homeostasis Human Human Activities Human Pathology Immune Immunology In Vitro Infiltration Inflammation Inflammatory Injury Interleukin-4 Investigation Investigational Therapies Ischemic Stroke Knock-out Knowledge Left Ventricular Remodeling Leukocytes Macrophage Measures Mediating Mus Myeloid Cells Myocardial Myocardial Infarction Myocarditis Myocardium Neutrophil Infiltration Organ Pathogenesis Pathology Pathway interactions Patients Phenotype Play Process Public Health Qualifying Regulation Reporting Research Role Signal Pathway Signal Transduction Site T-Lymphocyte Testing Therapeutic Time Translations Transplantation Immunology cell type chronic inflammatory disease clinical practice experience healing heart function improved in vivo inflammatory milieu innovation insight monocyte mortality mouse model myocardial injury novel novel therapeutic intervention novel therapeutics pre-clinical prevent recruit single cell technology targeted treatment tool vascular inflammation viral myocarditis

项目摘要

PROJECT SUMMARY/ABSTRACT Vascular inflammation is a key component of atherosclerosis that contributes to plaque instability and clinical cardiovascular events, including ischemic stroke, and myocardial infarction (MI). Despite decades of research, the immune mechanisms contributing to these processes remain largely unresolved. Among myeloid cells, monocytes/macrophages are believed to be major players in the pathogenesis of cardiovascular diseases (CVD). Emerging single-cell technologies have unveiled that the macrophage pool in CVD is vastly heterogeneous, containing a plethora of transcriptionally distinct subpopulations. In chronic inflammatory diseases, GATA3 is regarded as a master regulator of the phenotype of T-cells and other immune cells. However, the role of GATA3 in the regulation of the phenotype of macrophages is completely unknown. For the first time, we demonstrated that GATA3 was expressed in macrophages and GATA3+ macrophages accumulated into the myocardium after acute MI and adversely affected the cardiac function. In fact, the deficiency of GATA3+ macrophages led to a significant improvement of cardiac function after acute MI. Cell culture studies revealed that IL-33 stimulated the expression of GATA3 in macrophages. Our long term goal is to dissect the mechanism/s that regulates the phenotype and function of GATA3+ macrophages in CVD. Our rationale is that by identifying the mechanism/s that control the phenotype of GATA3+ macrophages in the setting of CVD will offer new therapeutic opportunities. In Specific Aim 1, we will utilize novel mouse models in combination with transplant immunology to test the hypothesis that macrophage-specific IL-33R signaling controls the recruitment and function of GATA3+ macrophages in CVD. Most studies aimed at characterizing the phenotypes of human macrophages are performed in vitro; however, the relevance to the function of macrophages in vivo is uncertain. The role of GATA3 signaling in the activity of human macrophages in vitro and in vivo is completely unknown. We have generated macrophage-specific humanized GATA3 sufficient mice as a novel preclinical platform to test the hypothesis that human GATA3 signaling controls the phenotype/function of macrophages after acute MI in Specific Aim 2. In depth knowledge of atherosclerotic plaques is a prerequisite to preventing and treating MI. We found that GATA3+ macrophages accumulated into atherosclerotic plaques, and GATA3 expression in macrophages is stimulated by cholesterol crystals. However, the function of GATA3+ macrophages in atherosclerosis is completely unknown. In Specific Aim 3, we will use atheroma-prone mouse models in combination with bone marrow transplantation to test the hypothesis that GATA3+ macrophage subset/s are atherogenic. The proposed research is innovative because we will investigate the effect of GATA3+ macrophages in CVD, a heretofore-unexamined process.

项目概要/摘要血管炎症是动脉粥样硬化的一个关键组成部分，导致斑块不稳定和临床症状心血管事件，包括缺血性中风和心肌梗塞（MI）。尽管经过数十年的研究，促成这些过程的免疫机制在很大程度上仍未得到解决。在骨髓细胞中，单核细胞/巨噬细胞被认为是心血管疾病发病机制的主要参与者（化学气相沉积）。新兴的单细胞技术揭示了 CVD 中的巨噬细胞库异质的，包含大量转录上不同的亚群。在慢性炎症在疾病中，GATA3 被认为是 T 细胞和其他免疫细胞表型的主要调节因子。然而，GATA3 在巨噬细胞表型调节中的作用尚不清楚。为了我们首次证明GATA3在巨噬细胞和GATA3+巨噬细胞中表达急性心肌梗死后，这些物质会积聚到心肌中，对心功能产生不利影响。事实上， GATA3+巨噬细胞的缺乏导致急性心肌梗死后心功能的显着改善。细胞培养研究表明 IL-33 刺激巨噬细胞中 GATA3 的表达。我们的长期目标是剖析调节 CVD 中 GATA3+ 巨噬细胞表型和功能的机制。我们的基本原理是通过确定控制 GATA3+ 巨噬细胞表型的机制 CVD的设置将提供新的治疗机会。在具体目标 1 中，我们将利用新颖的小鼠模型结合移植免疫学来检验巨噬细胞特异性 IL-33R 信号传导的假设控制 CVD 中 GATA3+ 巨噬细胞的募集和功能。大多数研究旨在表征人类巨噬细胞的表型是在体外进行的；然而，与功能的相关性巨噬细胞在体内的情况是不确定的。 GATA3信号在体外人巨噬细胞活性中的作用而体内则完全未知。我们已经生成了足够的巨噬细胞特异性人源化GATA3 小鼠作为新的临床前平台来测试人类 GATA3 信号控制的假设具体目标 2. 深入了解动脉粥样硬化急性心肌梗死后巨噬细胞的表型/功能斑块是预防和治疗心肌梗死的先决条件。我们发现GATA3+巨噬细胞聚集成动脉粥样硬化斑块和巨噬细胞中的 GATA3 表达受到胆固醇晶体的刺激。然而，GATA3+巨噬细胞在动脉粥样硬化中的功能尚不清楚。在具体目标 3 中，我们将使用易发生动脉粥样硬化的小鼠模型结合骨髓移植来测试假设 GATA3+ 巨噬细胞亚群是致动脉粥样硬化的。拟议的研究具有创新性，因为我们将研究 GATA3+ 巨噬细胞在 CVD 中的作用，这是一个迄今为止未经检验的过程。