Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis

动脉粥样硬化中的克隆扩张、胞吞作用抵抗和先天免疫

• 批准号: 10543819
• 负责人: Nicholas James Leeper
• 金额: $ 85.4万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543819
• 关键词: Atherosclerosis; Blood Vessels; Cardiovascular Diseases; Cells; Clonal Expansion; Color; Complement; Data; Development; Disease; Excision; Goals; Greek; Growth; Heart Diseases; Human; Learning; Malignant Neoplasms; Mission; Modeling; Myocardial Infarction; Natural Immunity; Patients; Phagocytes; Phenotype; Population; Research Personnel; Resistance; Smooth Muscle Myocytes; Specimen; Stroke; Testing; Tracer; Training; Transgenic Animals; United States; United States National Institutes of Health; Vascular Smooth Muscle; atherogenesis; biobank; flexibility; insight; interdisciplinary collaboration; next generation; novel; novel therapeutics; prevent; programs; single-cell RNA sequencing; stem; stem cells; stem-like cell; tool; translational therapeutics; vascular inflammation

PROJECT SUMMARY/ABSTRACT Recent studies have shown that the vascular smooth muscle cell (SMC) can ‘de-differentiate’ and undergo substantial ‘phenotypic modulation’ during atherogenesis. Novel lineage-tracing data revealed that a subset of these cells assume a ‘stem-like’ phenotype and undergo significant clonal expansion, likely potentiating plaque progression. Unfortunately, we do not yet know the mechanism by which these clonal populations arise, how they promote disease, or whether they can be targeted for translational purposes. The broad, long-term goal of this proposal is to precisely define how clonal expansion occurs and how to suppress it. In doing so, we will learn how to target the ‘atherosclerosis stem cell’ and develop novel therapies for heart disease. Using new preliminary data generated via single-cell RNA-seq analysis of multicolor lineage-tracer models, our team will test the hypothesis that ‘stem-like’ SMCs evade phagocytic removal (allowing them to undergo clonal expansion) and activate the complement cascade (causing them to exacerbate vascular inflammation). The project combines unique transgenic animals, highly specialized human biorepository specimens and new interdisciplinary collaborations. The program is focused on three broad efforts which will: 1. Determine if pro-phagocytic therapies can specifically prevent clonal expansion; 2. Determine whether the ‘stem-like’ SMC requires the classical complement cascade to promote disease; and 3. Determine if clonal SMC expansion also has translational relevance to human atherosclerosis. This proposal will provide important insights into the root causes of SMC plasticity and determine how programmed cell removal, or ‘efferocytosis’ (from Greek, meaning to carry the dead to the grave) contributes to atherosclerosis. Ultimately, discoveries made in this highly flexible R35 project will support the stated mission of the National Institutes of Health, provide tools for other HLBS investigators, train the next generation of investigators, and lead to the development of new translational therapies for patients with cardiovascular disease.

项目概要/摘要 最近的研究表明，血管平滑肌细胞（SMC）可以“去分化”并 新的谱系追踪数据显示，在动脉粥样硬化形成过程中经历了实质性的“表型调节”。 这些细胞的子集呈现“干状”表型并经历显着的克隆扩张，可能 不幸的是，我们还不知道这些克隆的作用机制。 人群的出现、它们如何促进疾病，或者它们是否可以作为转化目的的目标。 该提案的广泛、长期目标是精确定义克隆扩张如何发生以及如何 在此过程中，我们将学习如何针对“动脉粥样硬化干细胞”并开发新的药物。 使用通过单细胞 RNA-seq 分析生成的新初步数据来治疗心脏病。 多色谱系示踪模型，我们的团队将测试“茎状”SMC 逃避吞噬的假设 去除（允许它们进行克隆扩增）并激活补体级联（导致它们 该项目结合了独特的转基因动物，高度专业化。 人类生物样本库和新的跨学科合作该计划重点关注三个方面。 广泛的努力将： 1. 确定促吞噬细胞疗法是否可以特异性预防克隆扩增； 确定“干状”SMC 是否需要经典补体级联来促进疾病；3. 确定克隆 SMC 扩张是否也与人类动脉粥样硬化具有转化相关性。 将为了解 SMC 可塑性的根本原因提供重要见解，并确定细胞如何编程 移除或“efferocytosis”（来自希腊语，意思是将死者带入坟墓）会导致动脉粥样硬化。 最终，这个高度灵活的 R35 项目中的发现将支持国家实验室的既定使命 卫生研究院，为其他 HLBS 研究人员提供工具，培训下一代研究人员，以及 导致心血管疾病患者新转化疗法的开发。