Smooth muscle cell-derived cell fates and cellular interactions in atherosclerotic plaque stability in disease progression and regression.

平滑肌细胞衍生的细胞命运和细胞相互作用在疾病进展和消退中动脉粥样硬化斑块的稳定性。

• 批准号: 10567844
• 负责人: Muredach P Reilly
• 金额: $ 72.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567844
• 关键词: 8-Oxoguanine DNA Glycosylase; Acceleration; Affect; Arterial Fatty Streak; Atherosclerosis; Attenuated; Blood Vessels; Cardiovascular Diseases; Cell Lineage; Cell physiology; Cells; Clinical; Coupled; DNA; DNA glycosylase; Data; Diphtheria Toxin; Disease Progression; Disease regression; Etiology; Fibroblasts; Functional disorder; Genes; Genetic; Genetic Diseases; Genetic Variation; Goals; Histology; Human; Impairment; Inflammasome; Inflammatory; Lesion; Lipids; Location; Low-Density Lipoproteins; Macrophage; Modeling; Multiomic Data; Necrosis; Patients; Pilot Projects; RNA; Regulator Genes; Residual state; Resolution; Resources; Role; Shoulder; Signal Transduction; Smooth Muscle Myocytes; Source; Stable Disease; Testing; Transgenic Mice; Transgenic Model; Translations; Tretinoin; Variant; Vascular Smooth Muscle; Work; atheroprotective; biobank; cardiovascular disorder risk; cell type; clinically relevant; epigenetic marker; in situ sequencing; insight; mouse model; multiple omics; novel; novel therapeutic intervention; oxidative DNA damage; single-cell RNA sequencing; spatial integration; transcriptome sequencing

Residual cardiovascular disease (CVD) risk in patients on lipid lowering therapy is a major unmet clinical need. Our goal is to investigate mechanisms of plaque stabilization and destabilization focused on functions of vascular smooth muscle cell (SMC) derived cells (SDCs), and their crosstalk with macrophages (Mϕ), in mouse models and human CVD. We focus on SDC types, location and functions and their interactions with Mϕ in plaque stability in disease progression and regression. SMCs can transition through an intermediate state into atheroprotective, e.g., fibrochondrocyte (SMC-FbC), or atherogenic, e.g., SMC-derived macrophage-like (SMC-Mϕ) identities. Master regulators of SDC identities are emerging for protective (retinoic acid, Tcf21) and harmful (Klf4) types, but mechanisms are poorly understood. We hypothesize that SDC functions in lesion stability and clinical CVD are malleable and can be inferred from spatial and single-cell (sc) omics; SMC-Mϕ are inflammatory and activate bystander Mϕ to promote plaque instability; oxidative DNA (ox-DNA) damage regulates SDC identities and functions to destabilize lesions; and crosstalk of atherogenic SDCs and Mϕs promotes lesion instability and impairs regression. Aim 1 will determine locations and functions of SDC types in atherosclerosis progression and test if SMC-Mϕ and SDC ox-DNA damage drive atherogenic SMC identities and lesion instability while Aim 2 will address whether some SDCs promote and others curb plaque stabilization in atherosclerosis regression, and if regression is attenuated by SMC-Mϕ and SDC ox-DNA damage. In these Aims, we will; (1) integrate spatial hybridization-based RNA in situ sequencing (HybRISS), sc-omics and SMC lineage tracing to define identity, spatial functions, and master regulators of SDCs during lesion progression and regression, focusing on functions such as SMC-Mϕs inflammasome and impaired efferocytosis; (2) use a diphtheria toxin (Dtx) mouse model to track SMC-Mϕ and to test if depletion of SMC-Mϕ reduces lesion instability in progression and accelerates resolution; and (3) use an SMC-inducible 8-oxoguanine DNA glycosylase (OGG1) transgenic mouse model to test if SMC ox-DNA damage, which is increased in atherosclerosis, pushes SDCs to atherogenic identities. Aim 3 will test if specific SDC types and their regulatory genes promote clinical CVD. Using multi-omic data from the Munich Vascular Biobank, we will deploy an integrated strategy to go from descriptive studies in human plaques, to regulatory genetic variation in SDCs, to testing causal relationship of these variants with clinical CVD in large genetic data. Our work will provide mechanistic insight into the role of SDC types, their spatial functions, and crosstalk with Mϕ to achieve our overall goal of greater mechanistic understanding of factors affecting atherosclerotic plaque stability and instability. Human translation will establish clinical relevance, causality and context for new treatment strategies for CVD.

脂质降低治疗患者的残留心血管疾病（CVD）风险是主要的未满足的临床需求。 我们的目标是研究斑块稳定和不稳定的机制，该机制集中在血管的功能上 在小鼠模型中 和人类CVD。我们专注于SDC类型，位置和功能及其与斑块稳定性中M ϕ的相互作用 在疾病进展和回归中。 SMC可以通过中间状态过渡到动脉保护性， 例如，纤维软骨细胞（SMC-FBC）或动脉粥样硬化，例如SMC衍生的巨噬细胞样（SMC-Mϕ）身份。 SDC身份的主要调节剂正在为保护性（视黄酸，TCF21）和有害（KLF4）类型而出现， 但是机制知之甚少。我们假设SDC在病变稳定性和临床CVD中起作用 具有延展性，可以从空间和单细胞（SC）OMICS中推断出来； SMC-Mϕ是炎症的，激活 旁观者m ϕ促进斑块不稳定性；氧化DNA（OX-DNA）损伤调节SDC身份和 功能破坏病变；动脉粥样硬化和M ϕ的串扰促进了病变的不稳定性和 损害回归。 AIM 1将确定动脉粥样硬化进展中SDC类型的位置和功能 并测试SMC-Mϕ和SDC OX-DNA损伤是否驱动了动脉粥样硬化的SMC身份和病变不稳定性 2将解决某些SDC是否促进和其他SDC在动脉粥样硬化回归中的菌斑稳定， 如果通过SMC-Mϕ和SDC OX-DNA损伤减轻回归。在这些目标中，我们将； （1）集成 基于空间杂交的RNA原位测序（Hybriss），SC-omics和SMC谱系跟踪以定义 病变进展和回归期间SDC的身份，空间功能和主调节器，重点放在 诸如SMC-MϕS炎性体和肿瘤​​病障碍的功能； （2）使用白喉毒素（DTX）小鼠 跟踪SMC-Mϕ的模型并测试SMC-Mϕ的耗竭是否会减少进展中的病变不稳定性 加速分辨率； （3）使用SMC诱导的8-氧气DNA糖基酶（OGG1）转基因小鼠 测试在动脉粥样硬化中增加的SMC OX-DNA损伤是否会将SDC推向动脉粥样硬化 身份。 AIM 3将测试特定的SDC类型及其调节基因是否促进临床CVD。使用多摩变 来自慕尼黑血管生物库的数据，我们将采用综合策略，从描述性研究中 人斑块，用于调节SDC的调节遗传变异，以测试这些变体的因果关系 大遗传数据中的临床CVD。我们的工作将提供有关SDC类型的作用的机械洞察力 空间功能，并与M ϕ串扰，以实现我们对更大机械理解的总体目标 影响动脉粥样硬化斑块稳定性和不稳定性的因素。人翻译将建立临床相关性， CVD新治疗策略的因果关系和背景。