The role of nitrogen metabolism in smooth muscle cell phenotypic plasticity

氮代谢在平滑肌细胞表型可塑性中的作用

基本信息

  • 批准号:
    10535170
  • 负责人:
  • 金额:
    $ 3.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-12-19 至 2025-12-18
  • 项目状态:
    未结题

项目摘要

Coronary artery is the leading cause of death in the US. While lipid-lowering and anti-hypertensive drugs have helped decrease CAD-related mortality by approximately 50% since the 1980s, these therapies only modify CAD risk factors. To date, no approved drug acts at the vascular wall directly against atherosclerosis, the underlying cause of CAD. One opportunity to develop novel therapies is through genetics: CAD is partially heritable, and recent genome-wide association studies identified over 200 loci associated with elevated risk for CAD. While 40% of these CAD loci having established associations with known risk factors, the molecular and cellular mechanisms of the remaining 60% of the CAD loci are unknown. The majority of these unknown loci are predicted to function by regulating gene expression in the vascular wall where the disease develops. Vascular smooth muscle cells (SMCs), which make up the medial layer of arteries, play a critical role in the progression of atherosclerosis, the precursor to coronary artery disease. During initiation and progression of atherosclerosis, SMCs transdifferentiate from a quiescent (healthy) phenotype to a proliferative (pathological) phenotype representative of myogenic, osteochondrogenic, and macrophage-like phenotypes that contribute to plaque build-up. Identifying the molecular mechanisms driving SMC phenotypic plasticity will open up new avenues of treatment for CAD. Preservation analysis of co-expression networks from RNAseq data generated from the ascending aortas of 151 multi-ethnic smooth muscle cell donors cultured in quiescent and proliferative conditions, respectively, revealed phenotype-specific network architecture enriched for nitrogen metabolic processes. Previous studies have shown that metabolic pathways are not only involved in phenotypic changes of other cell types in the vascular wall, but also have the capability to drive them. Therefore, the goal of this proposal is to characterize the role nitrogen metabolism plays in SMC phenotypic plasticity and identify the key regulatory genes driving dysregulation. The project will address this problem through 2 aims. In aim 1, I will characterize the role nitrogen metabolism plays in SMCs during the progression of atherosclerosis using a combined approach of metabolomics, cell type marker identification, and cellular phenotyping assays in response to activation or silencing of the nitrogen metabolism pathway. In aim 2, I will create Bayesian networks (BNs) of genes involved in nitrogen metabolic processes using gene expression data and transcription factor-gene expression relationships generated from time-series experiments linking differentially expressed ATACseq peaks and differentially expressed RNAseq peaks in response to pro-atherogenic stimulus. I will then identify the key driver genes (KDs) of nitrogen metabolic pathways whose expression regulates the changes across the gene expression networks. Gain-of-function and loss-of-function experiments for KDs in SMCs using lentiviral particles will be completed with cellular phenotyping assays to quantify the impact on SMC proliferation, migration, and de-differentiation.
冠状动脉是美国的主要死因。虽然降脂和抗高血压药物 自20世纪80年代以来,这些疗法帮助降低了CAD相关死亡率约50%,但这些疗法仅改变了 CAD危险因素迄今为止,没有批准的药物直接作用于血管壁对抗动脉粥样硬化, CAD的根本原因开发新疗法的一个机会是通过遗传学:CAD部分是 遗传的,最近的全基因组关联研究确定了200多个与高风险相关的基因座, CAD.虽然这些CAD基因座中有40%与已知的危险因素有关,但分子和 其余60%的CAD基因座的细胞机制尚不清楚。这些未知基因座中的大多数 被预测通过调节疾病发展的血管壁中的基因表达来发挥作用。 血管平滑肌细胞(SMC),组成动脉的中层,在动脉粥样硬化中起关键作用。 动脉粥样硬化的进展,冠状动脉疾病的前兆。在开始和进展期间, 在动脉粥样硬化中,SMC从静止(健康)表型转分化为增殖(病理)表型。 表型代表肌源性、骨软骨形成性和巨噬细胞样表型, 牙菌斑积聚。确定驱动SMC表型可塑性的分子机制将开辟新的 CAD的治疗方法。从生成的RNAseq数据对共表达网络的保存分析 来自151个多种族平滑肌细胞供体的升支动脉, 条件下,分别揭示了氮代谢的表型特异性网络结构, 流程.以往的研究表明,代谢途径不仅参与表型的改变 血管壁中其他细胞类型的细胞,但也有能力驱动它们。因此,这一目标 建议是描述氮代谢在SMC表型可塑性中的作用,并确定关键因素。 调控基因驱动失调。该项目将通过两个目标来解决这个问题。在目标1中,我将 使用一种新的方法来表征氮代谢在动脉粥样硬化进展过程中在SMC中的作用, 代谢组学、细胞类型标志物鉴定和细胞表型分析的组合方法, 响应于氮代谢途径的激活或沉默。在目标2中,我将创建贝叶斯 使用基因表达数据的氮代谢过程中涉及的基因网络(BN), 从时间序列实验中产生的转录因子-基因表达关系, 表达的ATACseq峰和响应促动脉粥样硬化的差异表达的RNAseq峰 刺激。然后,我将确定氮代谢途径的关键驱动基因(KD),其表达 调节着基因表达网络的变化。功能获得和功能丧失实验 对于使用慢病毒颗粒的SMC中的KD,将通过细胞表型分析完成,以定量 影响SMC增殖、迁移和去分化。

项目成果

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