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

该R35提案代表了一个全面的长期计划，探讨了新机制和 与引起急性的动脉粥样硬化斑块的形成相关的治疗概念 心血管疾病（CVD）。年轻科学家的培训和心理也是该计划的关键部分。 PI多年来一直在没有中断的情况下持有多次NIH赠款，发表了动脉粥样硬化和 在最高影响期刊中的心脏代谢疾病，并具有训练年轻的训练记录非常成功 科学家成为独立的学术研究人员。该计划将探索新的，高度相互关联的概念 与存在主要差距的四个关键领域有关：（i）炎症和肿瘤病的分辨率（清除率 死细胞）; （ii）临床上最重要的动脉粥样硬化病变的病理生理学； （iii） 与高负胚细胞增多症相关的M氨基酸代谢； （iv）与衰老相关的克隆 造血（CH）。损害注入分辨率的过程，与促进的过程不同 炎症本身，炎症性有缺陷促进临床相关的坏死，薄贴的形成 斑块。该实验室的新工作表明（i）MS内部化多个凋亡细胞的能力（高负荷） 胚细胞增多症对于避免坏死斑块至关重要（Cell 2017）； （ii）与M代谢有关的途径 凋亡细胞衍生的氨基酸对于高负for吞作用至关重要。另一个令人兴奋的新概念 受初步数据支持的是，CH会加剧肿瘤和分辨率受损，这是 成为动脉粥样硬化CVD的主要年龄相关危险因素。该计划的总体愿景是研究 这些新区域首先使用（i）小鼠和人类M阐明了深入的机制； （ii）一般 改变小鼠以测试晚期菌斑进展中的原因。 R35还将探索治疗潜力 在临床前模型中这些想法中，有假设是，解决方案调解人疗法将具有效率和 与常规抗炎疗法相比，安全优势。然后，PI将使用灵活性和连续性 R35计划转向与人类研究有关的新方向。通过丰富的合作者网络 在哥伦比亚和其他地方 - 包括哥伦比亚的心血管和代谢精密医学计划 - 该计划将将新发现应用于（i）人类动脉瘤的分析； （ii）人类遗传学，包括 通过与Promis研究的合作，具有基因KO的受试者在分辨率/经肿瘤途径中的受试者； （iii）针对CRISPR/CAS9介导的人类单核细胞和IPSC衍生的MS的研究 基因工程，在该计划的机械和人类遗传数据的指导下。通过灵活性 R35计划的前瞻性性质，拟议的机械工作与人类的结合 研究将提供一个功率组合，以填补危险形式的关键空白。设计小说 治疗策略；并在这一关键研究领域培训和指导年轻科学家。 1