Genomic Regulation and Translational Potential of a Novel Smooth Muscle Cell-Derived Cell Type in Atherosclerosis

动脉粥样硬化中新型平滑肌细胞衍生细胞类型的基因组调控和转化潜力

• 批准号: 10371660
• 负责人: Huize Pan
• 金额: $ 13.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371660
• 关键词: Address; Advisory Committees; Apoptosis; Applications Grants; Area; Arterial Fatty Streak; Atherosclerosis; Attenuated; Award; Biochemical; Cardiovascular Diseases; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Complex; Data; Development; Disease Progression; Disease regression; EZH2 gene; Endothelial Cells; Epigenetic Process; Equilibrium; Fibroblasts; Gene Expression; Genes; Genomics; Human; Immunoprecipitation; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Investigation; Leadership; Lesion; Link; Liver X Receptor; Manuscripts; Mediating; Molecular; Molecular Target; Mus; Necrosis; Pathway interactions; Phase; Phenotype; Play; Preparation; Prevention; Program Development; Proliferating; RXR; Regulation; Repression; Research; Research Personnel; Research Training; Retinoic Acid Receptor; Role; Signal Transduction; Smooth Muscle Myocytes; Techniques; Testing; Thick; Time; Tretinoin; Vascular Smooth Muscle; Work; advanced disease; antagonist; atheroprotective; career; career development; cell type; cellular targeting; design; epigenetic regulation; gene repression; histological stains; inhibitor; insight; macrophage; monocyte; mouse model; novel; promoter; response; single-cell RNA sequencing; skills; stem cell biomarkers; stem cells; transdifferentiation; translational potential; western diet

Smooth muscle cells (SMCs) play major roles in atherosclerosis, a leading cause of cardiovascular disease (CVD). SMCs can be beneficial or detrimental in atherosclerosis, depending on their transdifferentiation trajectories into atheroprotective (e.g., fibroblast-like cell) or atherogenic (e.g., macrophage) cell types. My recent work, combining an SMC-lineage tracing murine model and single-cell RNA sequencing (scRNA-seq), revealed a novel SMC-derived cell type, “SEM” cell (termed because of co-expression of stem cell, endothelial cell, and monocyte markers). SMC-derived SEM-like cells have also been identified by other groups. SEM cells highly express genes related to proatherogenic functions (e.g., inflammation) and may be the precursors for other SMC- derived cell types (e.g., fibrochondrocyte, macrophage), through which SEM cells may modulate vulnerability and stability of atherosclerotic lesions. My proof of principle studies in mouse models showed that activation of retinoic acid (RA) signaling inhibited SMC to SEM cell transition, reduced atherosclerotic burden, and promoted fibrous cap stability in atherosclerosis. These findings suggest the following central hypotheses: 1) activation of RA signaling attenuates SMC to SEM cell transition by directly suppressing expression of key SEM cell marker genes; 2) activation of RA signaling represses proatherogenic functions (e.g., inflammation) of SEM cells during disease progression; 3) activation of RA signaling is beneficial in established atherosclerosis and accelerates disease regression by promoting SEM cell atheroprotective functions and differentiation trajectories while suppressing atheroprone features of SEM cells. These hypotheses will be addressed through the following aims: Aim 1 (K99 phase) will determine if RA signaling inhibits the SMC to SEM cell transition via RAR/RXR/EZH2- mediated repression of SEM cell marker genes; Aim 2 (K99 phase) will determine if RA signaling attenuates SEM cell inflammation during atherosclerosis progression through LXR-mediated repression of inflammatory genes; Aim 3 (R00 phase) will apply SMC-lineage tracing and atherosclerosis regression mouse models to determine if RA signaling drives differentiation trajectories of SEM cells towards atheroprotective rather than atherogenic cell types in advanced atherosclerosis (Aim 3A) and promotes SEM cell apoptosis and subsequent resorption via macrophage efferocytosis during disease regression (Aim 3B). The proposed studies will be accomplished in the setting of a comprehensive career development program designed to provide the candidate with scientific and leadership skills that facilitate the successful transition to an independent investigator in the field of atherosclerotic CVD. At the K99 phase, the candidate will continue to obtain expertise in molecular, cellular, and biochemical techniques as well as SMC-lineage tracing and mechanistic and functional investigation of RA signaling and SEM cells in atherosclerosis mouse models for progressing, advanced, and regressing lesions. The expert advisory team will guide the candidate in research training, manuscript and grant proposal preparation, and ultimately in the transition to an independence career over the course of the award period.

动脉粥样硬化是心血管疾病的主要病因之一，平滑肌细胞在动脉粥样硬化中起着重要作用 （心血管疾病）。SMC在动脉粥样硬化中可能是有益的，也可能是有害的，这取决于它们的转分化 进入动脉粥样硬化保护的轨迹（例如，成纤维细胞样细胞）或致动脉粥样硬化（例如，巨噬细胞）细胞类型。我最近 结合SMC谱系追踪小鼠模型和单细胞RNA测序（scRNA-seq）的工作揭示了 一种新的SMC衍生的细胞类型，“SEM”细胞（由于干细胞、内皮细胞和内皮细胞的共表达而命名）， 单核细胞标志物）。SMC衍生的SEM样细胞也已被其他小组鉴定。SEM细胞高度 表达与致动脉粥样硬化功能相关的基因（例如，炎症），并可能是其他SMC的前体- 衍生的细胞类型（例如，纤维软骨细胞，巨噬细胞），通过SEM细胞可以调节脆弱性 和动脉粥样硬化病变的稳定性。我在小鼠模型中的原理研究证明， 视黄酸（RA）信号转导抑制SMC向SEM细胞转化，减少动脉粥样硬化负荷，并促进 动脉粥样硬化中纤维帽的稳定性。这些发现提出了以下中心假设：1）激活 RA信号通过直接抑制关键SEM细胞标志物的表达来减弱SMC向SEM细胞的转变 基因; 2）RA信号传导的激活抑制促动脉粥样硬化功能（例如，炎症）的SEM细胞， 疾病进展; 3）RA信号传导的激活在已建立的动脉粥样硬化中是有益的，并且加速了疾病进展。 通过促进SEM细胞的动脉粥样硬化保护功能和分化轨迹， 抑制SEM细胞的动脉粥样硬化特征。这些假设将通过以下目标加以解决： 目的1（K99期）将确定RA信号传导是否通过RAR/RXR/EZH 2抑制SMC向SEM细胞转变。 介导的SEM细胞标志物基因的抑制; Aim 2（K99期）将确定RA信号传导是否减弱 通过LXR介导的炎症抑制在动脉粥样硬化进展过程中的SEM细胞炎症 Aim 3（R 00阶段）将应用SMC谱系追踪和动脉粥样硬化消退小鼠模型， 确定RA信号传导是否驱动SEM细胞的分化轨迹朝向动脉粥样硬化保护而不是 在晚期动脉粥样硬化（Aim 3A）致动脉粥样硬化细胞类型，并促进SEM细胞凋亡， 在疾病消退期间通过巨噬细胞巨噬细胞的再吸收（目的3B）。拟议的研究将是 完成了一个全面的职业发展计划，旨在为候选人提供 具有科学和领导技能，有助于成功过渡到独立调查员， 动脉粥样硬化CVD领域。在K99阶段，候选人将继续获得分子， 细胞和生物化学技术以及SMC谱系追踪和机制和功能研究 RA信号和SEM细胞在动脉粥样硬化小鼠模型中的进展，进展和消退 病变专家顾问团队将指导候选人进行研究培训，手稿和赠款提案 准备，并最终在过渡到一个独立的职业生涯在授予期间的过程中。