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

• 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
• 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

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.

项目摘要/摘要 血管炎症是动脉粥样硬化的关键组成部分，有助于斑块不稳定性和临床 心血管事件，包括缺血性中风和心肌梗塞（MI）。尽管进行了数十年的研究， 导致这些过程的免疫机制在很大程度上仍未解决。在髓样细胞中， 据信单核细胞/巨噬细胞是心血管疾病发病机理的主要参与者 （CVD）。新兴的单细胞技术已经公布了CVD中的巨噬细胞池 异质，包含大量转录不同的亚群。在慢性炎症中 疾病，GATA3被视为T细胞和其他免疫细胞表型的主要调节剂。 但是，GATA3在巨噬细胞表型调节中的作用是完全未知的。为了 第一次，我们证明了GATA3在巨噬细胞和GATA3+巨噬细胞中表达 急性MI后积聚到心肌中，并对心脏功能产生不利影响。实际上， GATA3+巨噬细胞的缺乏导致急性MI后心脏功能显着改善。细胞 培养研究表明，IL-33刺激了巨噬细胞中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 理由是通过识别控制GATA3+巨噬细胞表型的机制 CVD的设置将提供新的治疗机会。在特定的目标1中，我们将利用新颖的鼠标模型 结合移植免疫学，以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。大多数旨在表征的研究 人类巨噬细胞的表型是在体外进行的。但是，与 体内巨噬细胞尚不确定。 GATA3信号在体外人类巨噬细胞活性中的作用 体内是完全未知的。我们已经产生了巨噬细胞特异性的人性化GATA3足够 小鼠是一个新的临床前平台，以检验人GATA3信号传导控制的假设 在特定目标2中急性MI后巨噬细胞的表型/功能。在深入了解动脉粥样硬化的知识中 斑块是预防和治疗MI的先决条件。我们发现GATA3+巨噬细胞积累到 胆固醇晶体刺激了动脉粥样硬化斑块和巨噬细胞中的GATA3表达。 但是，GATA3+巨噬细胞在动脉粥样硬化中的功能是完全未知的。在特定的目标3中 我们将使用易触及的小鼠模型与骨髓移植一起测试 假设GATA3+巨噬细胞子群是动脉粥样硬化的。拟议的研究具有创新性，因为 我们将研究GATA3+巨噬细胞在CVD中的效果，CVD是一种迄今为止未经证实的过程。