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: 10565956
• 负责人: Ira A Tabas
• 金额: $ 97.13万
• 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/10565956
• 关键词: Acute; 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; Macrophage; Mediating; Mediator; 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; 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"phi"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"phi"s to internalize multiple apoptotic cells (high-burden efferocytosis) is critical to avoid necrotic plaques (Cell 2017); and (ii) a pathway related to M"phi" 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"phi"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"phi"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.

该R35提案代表了一个全面、长期的计划，该计划探索了新的机制和 与特殊类型动脉粥样硬化斑块形成相关的治疗概念 心血管疾病(CVD)。对青年科学家的培训和指导也是这一计划的关键部分。 多年来，PI连续多次获得NIH拨款，出版了关于动脉粥样硬化和 心脏代谢性疾病在影响最大的期刊上，并有非常成功的记录，培训年轻人 科学家成为独立的学术研究人员。该计划将探索高度相关的新概念 与存在重大差距的四个关键领域有关：(1)消炎和泡沫化(清除 (2)临床上最重要的少数动脉粥样硬化病变的病理生理学； S的氨基酸代谢与高负荷泡泡细胞增多有关；以及(Iv)与衰老相关的克隆 造血(CH)。损害炎症分解的过程，这与促进炎症分解的过程不同 炎症本身和有缺陷的泡出促进了临床上相关的坏死性薄帽的形成。 斑块。该实验室的新工作表明：(I)M“Phi”S内化多个凋亡细胞的能力(高负荷 泡腾作用)是避免坏死斑的关键(Cell 2017)；以及(Ii)与M“phi”代谢有关的途径 凋亡细胞衍生的氨基酸对高负荷的泡腾作用至关重要。另一个令人兴奋的新概念 初步数据支持的是，CH会加剧泡腾作用和分辨率受损，这是 成为动脉粥样硬化性心血管疾病的主要年龄相关危险因素。该计划的总体愿景是研究 这些新领域首先利用(I)小鼠和人的M“Phi”S来阐明深入的机制；以及(Ii)从遗传学的角度 改变小鼠以测试晚期斑块进展的原因。R35还将探索治疗潜力 这些想法在临床前模型中，假设解析中介治疗将具有疗效和 安全性优于传统的抗炎疗法。然后，PI将使用灵活性和连续性 R35计划进入与人体研究相关的新方向。通过丰富的合作者网络 在哥伦比亚大学和其他地方--包括哥伦比亚大学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)人类动脉粥样硬化的分析；(Ii)人类遗传学，包括 通过与PROMIS研究合作，具有分解/泡吞噬途径中基因的KO的受试者； 和(Iii)人单核细胞和IPSC来源的M“Phi”S对CRISPR/Cas9介导的研究 基因工程，由该计划的机械学和人类基因数据指导。通过灵活性 R35方案的前瞻性，拟议的机械性工作和人类工作的结合 研究将提供一种力量组合，以填补斑块形成的危险程度的关键空白；设计新的 治疗战略；以及在这一关键研究领域培训和指导年轻科学家。