A Mechanistic and Translational Research Program Linking Impaired Resolution, Defective Efferocytosis, and Clonal Hematopoiesis to the Formation of Clinically Dangerous Atherosclerotic Plaques

一项将分辨率受损、胞吞作用缺陷和克隆造血与临床危险动脉粥样硬化斑块形成联系起来的机制和转化研究项目

• 批准号: 10112953
• 负责人: Ira A Tabas
• 金额: $ 97.14万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-07 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10112953
• 关键词: Acute; Address; Aging; Amino Acids; Anti-Inflammatory Agents; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Blood Cells; CRISPR/Cas technology; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Collaborations; Complement; Dangerousness; Data; Etiology; Functional disorder; Genes; Genetic Engineering; Genetic study; Grant; Hematopoiesis; Human; Human Engineering; Human Genetics; Impairment; Inflammation; Interruption; Journals; Knowledge; Lead; Link; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolism; Minority; Mus; Nature; Necrosis; Pathway interactions; Pre-Clinical Model; Process; Publishing; Research; Research Personnel; Resolution; Risk Factors; Safety; Scientist; Testing; Therapeutic; Thinness; Tissues; Training; United States National Institutes of Health; Vision; Work; age related; amino acid metabolism; clinically relevant; design; flexibility; induced pluripotent stem cell; macrophage; monocyte; novel therapeutic intervention; precision medicine; programs; translational research program

This R35 proposal represents a comprehensive, long-term program that explores new mechanisms and therapeutic concepts related to the formation of the unique types of atherosclerotic plaques that cause acute cardiovascular disease (CVD). The training and mentoring of young scientists is also a key part of this program. The PI has held multiple NIH grants without interruption for many years, publishes on atherosclerosis and cardiometabolic disease in the highest impact journals, and has a highly successful record of training young scientists to be independent academic researchers. The program will explore new, highly interrelated concepts related to four key areas in which major gaps exist: (i) inflammation resolution and efferocytosis (clearance of dead cells); (ii) pathophysiology of the minority of atherosclerotic lesions that are most clinically important; (iii) amino acid metabolism in Ms as it relates to high-burden efferocytosis; and (iv) aging-related clonal hematopoiesis (CH). Processes that impair inflammation resolution, which are distinct from those that promote inflammation per se, and defective efferocytosis promote the formation of clinically relevant necrotic, thin-capped plaques. The lab's new work indicates that (i) the ability of Ms to internalize multiple apoptotic cells (high-burden efferocytosis) is critical to avoid necrotic plaques (Cell 2017); and (ii) a pathway related to M metabolism of apoptotic cell-derived amino acids is critical for high-burden efferocytosis. Another exciting new concept supported by preliminary data is that impaired efferocytosis and resolution are exacerbated by CH, which is emerging as a major age-related risk factor for atherosclerotic CVD. The overall vision of the program is to study these new areas by first using (i) mouse and human Ms to elucidate in-depth mechanisms; and (ii) genetically altered mice to test causation in advanced plaque progression. The R35 will also explore the therapeutic potential of these ideas in pre-clinical models, with the hypothesis that resolution mediator therapy will have efficacy and safety advantages over conventional anti-inflammatory therapy. The PI will then use the flexibility and continuity of the R35 program to move into new directions related to human studies. Through a rich network of collaborators at Columbia and elsewhere—including Columbia's Cardiovascular and Metabolic Precision Medicine program— the program will apply the new discoveries to (i) analyses of human atheroma; (ii) human genetics, including subjects with KOs of genes in resolution/efferocytosis pathways through a collaboration with the PROMIS study; and (iii) studies with human monocyte- and iPSC-derived Ms that are amenable to CRISPR/Cas9-mediated genetic engineering, as guided by the program's mechanistic and human genetic data. Through the flexibility and forward-looking nature of the R35 program, the combination of the proposed mechanistic work and human studies will provide a power combination to fill in critical gaps in how dangerous plaque form; to devise novel therapeutic strategies; and to train and mentor young scientists in this critical area of research. 1

这项 R35 提案代表了一项全面的长期计划，旨在探索新的机制和 与导致急性动脉粥样硬化斑块形成的独特类型相关的治疗概念 心血管疾病（CVD）的培训和指导也是该计划的关键部分。 PI 多年来不间断地持有多项 NIH 资助，发表有关动脉粥样硬化和 心脏代谢疾病在最具影响力的期刊上发表，并在培训年轻人方面拥有非常成功的记录 该计划将探索新的、高度相关的概念。 与存在重大差距的四个关键领域相关：（i）炎症消退和胞吞作用（清除 (ii) 少数临床上最重要的动脉粥样硬化病变的病理生理学； Ms 中的氨基酸代谢，因为它与高负荷胞吞作用有关；以及 (iv) 与衰老相关的克隆 损害炎症消退的过程与促进炎症消退的过程不同。 炎症本身和有缺陷的胞吞作用促进临床相关坏死、薄帽的形成 该实验室的新工作表明（i）Mfs 内化多个凋亡细胞（高负荷）的能力。 胞吞作用）对于避免坏死斑块至关重要（Cell 2017）；以及 (ii) 与 Mf 代谢相关的途径； 凋亡细胞衍生的氨基酸对于高负荷胞吞作用至关重要。 初步数据支持的是，CH 加剧了胞吞作用和分辨率受损，这是 正在成为动脉粥样硬化性 CVD 的主要年龄相关危险因素。该计划的总体目标是研究。 首先使用小鼠和人类 Mf 来阐明这些新领域的深入机制；以及 改造小鼠以测试晚期斑块进展的因果关系，R35 还将探索其治疗潜力。 这些想法在临床前模型中的应用，假设解决中介疗法将有效并且 与传统抗炎治疗相比，PI 将具有灵活性和连续性的安全优势。 R35 计划通过丰富的合作者网络进入与人类研究相关的新方向。 在哥伦比亚和其他地方——包括哥伦比亚的心血管和代谢精准医学项目—— 该计划将把新发现应用于（i）人类动脉粥样硬化分析，包括（ii）人类遗传学； 通过与 PROMIS 研究合作，受试者在解析/胞吞作用途径中基因被敲除； (iii) 对人类单核细胞和 iPSC 衍生的 Mfs 进行研究，这些 Mfs 适合 CRISPR/Cas9 介导 基因工程，以程序的机械和人类基因数据为指导，具有灵活性。 R35计划的前瞻性和所提出的机械工作与人类的结合 研究将提供一种强大的组合来填补危险斑块形成方式的关键空白，从而设计新颖的产品； 战略；并培训和指导这一关键研究领域的年轻科学家。 1