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.

平滑肌细胞（SMC）在Attrorcolreosis中起主要作用，这是心血管疾病的主要原因 （CVD）。 轨迹进入动脉保护性（例如成纤维细胞样细胞）或动脉粥样硬化（例如巨噬细胞）。 工作，结合了SMC-Linege追踪鼠模型和单细胞RNA测序（SCRNA-SEQ），揭示了 一种新型的SMC衍生细胞类型“ SEM”细胞（称为干细胞，内皮细胞的共表达，以及 单核细胞标记） 与正确的功能（例如炎症）有关的表达基因，可能是其他SMC-的前体 派生的细胞类型（例如纤维软骨细胞，巨噬细胞），SEM细胞可能会模块脆弱性 和动脉粥样硬化病变的稳定性。 视黄酸（RA）信号传导抑制了SMC的半化，减轻了动脉粥样硬化负担并促进 动脉粥样硬化中的纤维帽稳定性。 RA信号通过直接抑制关键SEM细胞标记的表达来减轻SMC到SEM细胞的过渡 基因; 2）RA信号传导的激活抑制了SEM细胞的促进功能（例如，炎症） 疾病进展； 3）RA信号的激活对已建立的动脉粥样硬化是有益的 通过促进疾病回归 支持SEM细胞的动脉op舌特征。 AIM 1（K99相）将确定RA信号传导是否抑制SMC通过RAR/RAR/RXR/EZH2-销售过渡 SEM细胞标记基因的介导的AIM 2（K99相）将确定RA信号是否减弱 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 基因; AIM 3（R00阶段）将应用SMC-LINEGE追踪和动脉粥样硬化回归小鼠模型 确定RA信号传导是否驱动SEM细胞的区分轨迹向朝向动脉保护区而不是 晚期动脉粥样硬化（AIM 3A）中的动脉粥样细胞类型，并促进SEM细胞凋亡，随后 通过疾病回归期间的巨噬细胞肿瘤病（AIM 3B）。 在旨在为候选人提供的全面职业发展计划的设置中完成 具有科学和领导能力，促进成功过渡到独立研究者 动脉粥样硬化的CVD领域。 蜂窝和生化技术作为劳格跟踪以及机械和功能投资 RA信号传导和半度 病变。 在整个奖项期间，准备向独立职业过渡到独立职业。