Role of TET dioxygenase associated immune mechanisms in cardiac injury and repair

TET双加氧酶相关免疫机制在心脏损伤和修复中的作用

• 批准号: 9903438
• 负责人: Yun Huang
• 金额: $ 43.66万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903438
• 关键词: Ablation; Address; Advanced Development; Aging; Animals; Anterior; Arteries; Ascorbic Acid; Atherosclerosis; Blood Cells; Bone Marrow; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cells; Cicatrix; Clinic; Clonal Expansion; Clone Cells; Collaborations; Coronary; Coronary heart disease; DNA; DNA Methylation; DNA Modification Process; Data; Dimensions; Dioxygenases; Dissection; Distal; Enhancers; Epigenetic Process; Exhibits; Fibrosis; Functional disorder; Genes; Genetic Transcription; Genomics; Goals; Growth; Heart; Heart Injuries; Heart failure; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Human; Immune; Impairment; Individual; Infarction; Inflammasome; Inflammation; Inflammatory; Ischemia; Knockout Mice; Knowledge; Laboratories; Left; Ligation; Mediating; Mission; Molecular; Monitor; Mus; Mutation; Myelogenous; Myeloid Cells; Myocardial Infarction; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Physiological; Pilot Projects; Positioning Attribute; Prevention; Process; Protein Family; Protein translocation; Reporter; Reporter Genes; Resolution; Risk; Rodent Model; Role; Scheme; Somatic Mutation; Spleen; Stress; Testing; Tetanus Helper Peptide; Time; Tissues; Transcriptional Regulation; Transgenic Organisms; United States National Institutes of Health; base; cardiac repair; cardiovascular disorder risk; clinically relevant; demethylation; empowered; epigenetic therapy; epigenome; epigenome editing; exome sequencing; healing; heart damage; heart function; high risk; in vivo; injury and repair; innovation; insight; ischemic injury; loss of function; macrophage; monocyte; mouse model; new therapeutic target; novel; oxidation; pre-clinical; prevent; public health relevance; repaired; response; single-cell RNA sequencing; tissue repair; tool; transcription factor; transcriptomics

Project Summary/ Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is defined as an expansion of somatic hematopoietic blood cell clone in individual without hematological disorders. Recent exome sequencing identified hematopoietic stem and progenitor cells (HSPCs) with frequent mutations of epigenetic regulators (e.g., the DNA methylcytosine dioxygenase TET2) that exhibited growth advantage with clonal expansion during aging. Interestingly, CHIP individuals with somatic TET2 mutations tend to have high risk of coronary cardiovascular diseases (CVD). This discovery heralds the advent of a molecular era in the dissection of novel pathogenic mechanisms underlying CHIP-CVD convergence. In animal studies that mimic clonal hematopoiesis, Tet2 LOF has been found to accelerate atherosclerosis and heart failure. While these studies provided detailed phenotypic characterizations, the underlying molecular mechanisms and the causal relations between TET2 LOF in CHIP and increased CVD risk remain largely unresolved. The PI’s laboratory has developed a set of unique tools to address this critical clinically-relevant knowledge gap, including (i) tissue specific Tet2-deficient mouse models (specific ablation of Tet2 in the myeloid lineage or in HSPCs) with reporter genes to enable real-time lineage tracing in vivo during cardiac injury; and (ii) dCas9 based epigenome editing tools that allow the interrogation of causal effects between epigenotypes and phenotypes. The team proposes to test the hypothesis that Tet2 controls the activity of enhancers that regulate the expression of key genes required for maintaining the proper function of monocytes/ macrophages in the reparative response to ischemic injury (e.g., myocardial infarction or MI). Aim 1 will address how Tet2 loss impairs myeloid cells and HSPCs that actively participate in the post-MI cardiac repair process. Aim 2 will address how Tet2 deficiency disrupts enhancer activities in key genes that are essential for proinflammatory to reparative monocyte conversion, thereby perturbing the biphasic post-MI response of monocyte to compromise timely resolution of inflammation and cardiac repair. The idea of restoring Tet2/5hmC function will be further tested to intervene post-MI tissue repair. This study introduces a new dimension to dissect CVD pathogenesis by focusing on the interplay between the cardiovascular system and the immune-hematopoietic system. Completion of this project is anticipated to yield novel insights on how somatic TET2 mutations-associated clonal hematopoiesis increases the risk of cardiovascular disease (CVD) and impairs cardiac function under stress. More clinically relevant, discoveries made in this study are also expected to establish the preclinical rationale for targeting defective epigenetic regulators to prevent and treat CVD.

项目摘要/摘要 不确定电势（CHIP）的克隆造血作用定义为体细胞造血的膨胀 血细胞克隆在没有血液学疾病的个体中。最近确定的外显子组测序 造血茎和祖细胞（HSPC），具有表观遗传调节剂的频繁突变（例如， DNA甲基胞嘧啶二氧酶TET2）在衰老过程中暴露了克隆膨胀的生长优势。 有趣的是，具有躯体TET2突变的芯片个体往往具有高风险的冠状动脉血管 疾病（CVD）。这一发现预示了新型致病性解剖中分子时代的冒险 CHIP-CVD收敛的基础机制。在模仿克隆造血的动物研究中，tet2 lof 已经发现加速了动脉粥样硬化和心力衰竭。这些研究提供了详细的 表型特征，潜在的分子机制和TET2之间的因果关系 芯片中的LOF和CVD风险增加在很大程度上尚未解决。 PI的实验室已经开发了一套 解决此至关重要的知识差距的独特工具，包括（i）特定的TET2缺陷型 鼠标模型（特定于髓样谱系中的TET2或HSPC中的TET2消融）用报告基因启用 心脏损伤期间体内实时谱系追踪； （ii）基于DCAS9的表观基因组编辑工具，允许 对表观型和表型之间因果关系的询问。团队提议测试 TET2控制增强子的活性的假设，这些增强子的活性调节了所需的关键基因的表达 维持单核细胞/巨噬细胞在对缺血性损伤的修复反应中的适当功能（例如， 心肌梗塞或MI）。 AIM 1将解决TET2损失如何损害主动的髓样细胞和HSPC 参加MI后心脏修复过程。 AIM 2将解决TET2缺乏症如何破坏增强器 关键基因的活性对于促炎至高单核细胞的转化至关重要，从而 扰动单核细胞对及时解决炎症和 心脏修复。恢复TET2/5HMC功能的想法将进一步测试以干预MI组织后修复。 这项研究引入了一个新的维度，以剖析CVD发病机理 心血管系统和免疫 - 毛to骨系统。预计该项目的完成将产生 关于体细胞TET2突变相关的克隆造血的新见解会增加患的风险 心血管疾病（CVD），并在压力下损害心脏功能。更临床相关的发现 预计在这项研究中制定的将建立临床前原理来靶向有缺陷的表观遗传 预防和治疗CVD的监管机构。