Clonal expansion, resistance to efferocytosis and innate immunity in atherosclerosis

项目总结/摘要 最近的研究表明，血管平滑肌细胞（SMC）可以“去分化”， 在动脉粥样硬化形成过程中经历实质性的“表型调节”。新的谱系追踪数据显示， 这些细胞亚群呈现“干细胞样”表型并进行显著的克隆扩增， 促进斑块进展。不幸的是，我们还不知道这些克隆的机制， 人口的出现，它们如何促进疾病，或者它们是否可以被靶向用于翻译目的。 这项提议的广泛的、长期的目标是精确地定义克隆扩张是如何发生的， 在这样做的过程中，我们将学习如何靶向“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， 在谱系示踪模型中，我们的团队将测试“干细胞样”SMC逃避吞噬细胞的假设。 清除（允许它们进行克隆扩增）并激活补体级联（导致它们 加重血管炎症）。该项目结合了独特的转基因动物，高度专业化， 人类生物标本库和新的跨学科合作。该计划侧重于三个 广泛的努力，将：1。确定促吞噬细胞疗法是否可以特异性地防止克隆扩增; 2. 确定“干细胞样”SMC是否需要经典补体级联来促进疾病;和3. 确定克隆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 将提供重要的见解SMC可塑性的根本原因，并确定如何编程细胞 去除，或'红细胞增多症'（来自希腊语，意思是携带死者到坟墓）有助于动脉粥样硬化。 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科学院的既定使命。 卫生研究所，为其他HLBS研究人员提供工具，培训下一代研究人员， 从而为心血管疾病患者开发新的转化疗法。

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.