The epigenetic regulation of inflammation in tissue repair and vascular disease

组织修复和血管疾病中炎症的表观遗传调控

• 批准号: 10582010
• 负责人: Katherine Ann Gallagher
• 金额: $ 110.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2030-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582010
• 关键词: Abdominal Aortic Aneurysm; Aneurysm; Animal Model; Animals; Area; Atherosclerosis; Automobile Driving; Award; Biological Markers; Cardiovascular Diseases; Cells; Chromatin; Chronic; Clinic; Data; Development; Enzymes; Epigenetic Process; Etiology; Fibroblasts; Goals; Grant; Human; Inflammation; Innate Immune Response; Laboratories; Macrophage; Myeloid Cells; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral; Phenotype; Process; Prostaglandins; Publishing; Recovery; Regulation; Research; Research Personnel; Role; SARS-CoV-2 infection; Seminal; Sepsis; Shapes; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Therapeutic; Tissues; Vascular Diseases; Work; chemokine; coronavirus disease; epigenetic regulation; immunoregulation; injured; interest; keratinocyte; metabolomics; monocyte; novel; novel marker; novel therapeutics; programs; recruit; therapeutic target; tissue injury; tissue regeneration; tissue repair; validation studies

PROJECT SUMMARY The overarching theme for our research program over the past 10 years has been to better understand the etiology and pathogenesis of chronic inflammation in tissue repair processes and vascular disease, with a particular interest in how epigenetics influences the innate immune response and shapes pathologic and homeostatic processes. Our laboratory has contributed seminal studies related to 1) epigenetic regulation of myeloid cells that alter inflammation in abdominal aortic aneurysms (AAA), 2) regulation of macrophage phenotypes by chromatin modifying enzymes (CMEs) during tissue repair, 3) prostaglandin regulation of macrophage plasticity in the setting of tissue repair, 4) chemokines and other signaling pathways driving monocyte recruitment to injured tissue and tissue macrophage phenotypes, 5) epigenetic alterations that impact macrophage function in COVID-19 infection, 6) metabolomic and other biomarker studies in tissue regeneration and cardiovascular disease, 7) role of epigenetic regulation of macrophages following recovery from sepsis. Our work has utilized animal models to carry out mechanistic studies and patient-derived cells and tissues to confirm relevant pathways, identify therapeutic targets and characterize novel biomarkers. Based on our previously published observations and novel preliminary data, our laboratory is broadly focused in 4 main areas. The first serves as a continuation and expansion of HL156274 grant (currently in year 2) to complete and advance therapeutically relevant studies of JMJD3 and other critical CMEs in AAA development. The second goal will serve as renewal of HL137919 and allow us explore JAK/STAT signaling in tissue macrophages and blood monocytes and the downstream regulation of CMEs and subsequent inflammation in a variety of conditions (tissue regeneration, AAAs and post-sepsis recovery). The third goal will be to explore the interactions between structural cells (SMCs, keratinocytes, fibroblasts) and myeloid cells in the setting of tissue regeneration and AAA development. The fourth will be an expansion into the area of peripheral atherosclerosis where we will explore epigenetic regulation of macrophage phenotype/function in the setting of peripheral atherosclerotic disease (PAD). This emerging investigator award (EIA) mechanism will allow us to extend our studies in each of these areas and will allow for mechanistic understanding of the role of epigenetic regulation of macrophage phenotypes in the pathogenesis of a breadth of cardiovascular disease processes including tissue regeneration, aneurysm formation and peripheral atherosclerosis. It will also allow our laboratory to complete proof-of-concept and validation studies needed in both animals and humans to advance new therapies to the clinics for treatment of cardiovascular diseases.

项目摘要 过去十年来我们的研究计划的总体主题是更好地了解 组织修复过程和血管疾病中慢性炎症的病因和发病机理， 对表观遗传学如何影响先天免疫反应并塑造病理和 稳态过程。我们的实验室已促进了与1）表观遗传调节有关的开创性研究。 改变腹主动脉瘤中炎症的髓样细胞（AAA），2）调节巨噬细胞 在组织修复过程中通过染色质修饰酶（CME）进行的表型，3）前列腺素调节 在组织修复环境中的巨噬细胞塑性，4）趋化因子和其他信号传导途径驱动 单核细胞募集到受伤的组织和组织巨噬细胞表型，5）表观遗传学改变 在COVID-19感染中影响巨噬细胞功能，6）组织中代谢组和其他生物标志物研究 再生和心血管疾病，7）恢复后巨噬细胞表观遗传调节的作用 来自败血症。我们的工作利用动物模型进行机械研究和患者衍生的细胞，以及 组织以确认相关途径，确定治疗靶标并表征新型生物标志物。基于 我们先前发表的观察结果和新的初步数据，我们的实验室广泛关注4个主要 区域。第一个是HL156274 Grant（目前在2年级）的延续和扩展，以完成 并在AAA开发中对JMJD3和其他关键CME进行治疗相关研究。这 第二个目标将作为HL137919的更新，并让我们探索组织中的JAK/Stat信号 巨噬细胞和血液单核细胞以及CME的下游调节以及随后的炎症 多种疾病（组织再生，AAA和销售后恢复）。第三个目标是探索 结构细胞（SMC，角质形成细胞，成纤维细胞）和髓样细胞之间的相互作用 组织再生和AAA发育。第四个将是向周围区域的扩展 动脉粥样硬化，我们将探索巨噬细胞表型/功能的表观遗传调节。 周围动脉粥样硬化疾病（PAD）。这个新兴调查员奖（EIA）机制将使我们能够 扩展我们在每个领域的研究 在心血管疾病过程广度的发病机理中调节巨噬细胞表型 包括组织再生，动脉瘤形成和周围动脉粥样硬化。这也将允许我们 实验室以完成动物和人类所需的概念证明和验证研究 诊所的新疗法治疗心血管疾病。