Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis

项目摘要/摘要 最近的研究表明，血管平滑肌细胞(SMC)可以去分化和 在动脉粥样硬化形成过程中经历大量的“表型改变”。新的血统追踪数据显示， 这些细胞中的一个亚群呈现类似干细胞的表型，并可能经历显著的克隆性扩张 促进斑块的发展。不幸的是，我们还不知道这些克隆人 人口的增加，他们如何促进疾病，或者他们是否可以成为翻译目的的目标。 这项提议的广泛的长期目标是精确地定义克隆扩张是如何发生的以及如何发生的。 来压制它。在这样做的过程中，我们将学习如何针对“动脉粥样硬化干细胞”，并开发新的 心脏病的治疗方法。使用通过单细胞rna-seq分析产生的新的初步数据 多色谱系示踪剂模型，我们的团队将检验这一假说，即“干状”的SMC逃避吞噬 移除(允许它们进行克隆性扩张)并激活补体级联(导致它们 加剧血管炎症)。该项目结合了独特的转基因动物，高度专业化 人类生物库标本和新的跨学科合作。该计划的重点是三个方面 广泛的努力将：1。确定亲吞噬细胞疗法是否可以特异性地防止克隆性扩张； 确定“干状”的SMC是否需要经典的补体级联来促进疾病； 确定克隆性SMC扩增是否也与人类动脉粥样硬化有翻译相关性。这项建议 将为SMC可塑性的根本原因提供重要的见解，并确定编程细胞如何 移除或“胞吐”(希腊语中意为将死者抬入坟墓)会导致动脉粥样硬化。 最终，在这个高度灵活的R35项目中所取得的发现将支持国家 卫生研究所，为其他HLBS调查人员提供工具，培训下一代调查人员，以及 导致为心血管疾病患者开发新的转化性疗法。

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.