Metabolic and epigenetic reprogramming in the inflamed endothelium

发炎内皮的代谢和表观遗传重编程

• 批准号: 10793759
• 负责人: Audrey Cleuren
• 金额: $ 26.17万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10793759
• 关键词: Acetyl Coenzyme A; Acute; Affect; Blood; Cell physiology; Cells; Disease; Endothelial Cells; Endothelium; Epigenetic Process; Functional disorder; Glycolysis; High-Throughput Nucleotide Sequencing; Histone Acetylation; Human; Inflammation; Inflammatory; Lead; Location; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Modification; Molecular; Natural Immunity; Oklahoma; Physiological; Play; Research; Role; Stimulus; Testing; Tissues; cell type; endothelial dysfunction; histone modification; human disease; in vitro Assay; in vivo; inhibitor; insight; metabolic phenotype; therapeutic target; transcriptomics; vascular bed

Endothelial cells (ECs) form a dynamic interface between the blood and underlying tissue. Consistent with their specialized functions across vascular beds and the ability to rapidly respond to different (patho)physiological stimuli, ECs are both remarkably heterogeneous and highly metabolically active. Furthermore, given its strategic location the endothelium plays a key role in inflammation, which underlies many human diseases. Recent studies have shown that inflammation-induced EC dysfunction coincides with changes in metabolic pathways, particularly enhanced glycolysis. As a result, cells can accumulate metabolic intermediates such as acetyl-CoA. In addition to their known roles in metabolism, these metabolites are also important in mediating epigenetic processes such as histone acetylation, and thereby regulate cell function. While histone modifications are in principle reversible, they can be retained and lead to cellular memory. This is not only important for cell type identity, but also plays a role in innate immunity. However, whether inflammation-induced metabolic reprogramming in ECs can directly affect epigenetic modifications and cell function, and/or lead to cellular memory, is not known. Therefore, this project proposes two specific aims to test the hypothesis that inflammation-induced endothelial cell dysfunction is mediated by increased glycolysis and histone acetylation, which can subsequently lead to a sustained epigenetic signature. Aim 1 will evaluate the in vivo effects of acute inflammation on cellular function in an EC-specific manner using various metabolic phenotyping and high-throughput sequencing approaches, both in the absence and presence of a glycolysis inhibitor. In addition, targeted spatial transcriptomics will be employed to determine the contribution of distinct EC subsets in inflammation-induced endothelial dysfunction. In aim 2 we will perform in vitro assays using human ECs to further study the molecular mechanisms underlying metabolic reprogramming and epigenetic modifications under inflammatory conditions, and determine whether these modifications can be retained and lead to cell memory. The results obtained in this project will provide valuable insights into EC (dys)function, and have the potential to identify therapeutic targets for metabolism- and/or epigenetic-centric treatment of inflammation-related disorders.

内皮细胞（EC）在血液和下层组织之间形成动态界面。与 它们在血管床上的专业功能以及快速响应不同的能力 （病原）生理刺激，EC是明显的异质性和高度代谢活跃的。 此外，鉴于其战略位置，内皮在炎症中起关键作用，这是 许多人类疾病。最近的研究表明，炎症诱导的EC功能障碍与 代谢途径的变化，特别是增强的糖酵解。结果，细胞可以积累代谢 中间体，例如乙酰辅酶A。除了它们在代谢中的已知作用外，这些代谢也是 对于介导的表观遗传过程，例如组蛋白乙酰化以及调节细胞功能很重要。 尽管组蛋白的修饰原则上是可逆的，但可以保留并导致细胞记忆。这 不仅对细胞类型的身份很重要，而且在先天免疫中起作用。但是，是否 ECS中炎症诱导的代谢重编程可以直接影响表观遗传修饰和细胞 功能和/或导致蜂窝记忆尚不清楚。因此，该项目提出了两个具体目标 检验炎症诱导的内皮细胞功能障碍的假设是通过糖酵解增加介导的 和组蛋白乙酰化，随后会导致持续的表观遗传学特征。 AIM 1将评估 急性炎症对细胞功能的体内影响以EC特异性的方式使用各种代谢 在不存在和存在糖酵解的情况下，表型和高通量测序方法 抑制剂。此外，将采用有针对性的空间转录组学来确定不同的贡献 炎症引起的内皮功能障碍的EC集。在AIM 2中，我们将使用 人类EC进一步研究代谢重编程和表观遗传学的分子机制 在炎症条件下进行修改，并确定是否可以保留这些修改，并且 导致细胞内存。该项目中获得的结果将为EC（DYS）功能提供宝贵的见解， 并有可能确定代谢和/或以表观遗传治疗的治疗靶标的 与炎症有关的疾病。