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）在血液和皮下组织之间形成动态界面。符合 它们跨血管床的专门功能以及对不同情况快速反应的能力 在（病理）生理刺激下，EC 具有显着的异质性和高度代谢活性。 此外，鉴于其战略位置，内皮在炎症中发挥着关键作用，这是炎症的基础 许多人类疾病。最近的研究表明，炎症引起的 EC 功能障碍与 代谢途径的变化，特别是糖酵解的增强。结果，细胞可以积累代谢 乙酰辅酶A等中间体。除了在新陈代谢中的已知作用外，这些代谢物还 在介导组蛋白乙酰化等表观遗传过程中很重要，从而调节细胞功能。 虽然组蛋白修饰原则上是可逆的，但它们可以被保留并导致细胞记忆。这 不仅对于细胞类型识别很重要，而且在先天免疫中也发挥着作用。然而，无论 炎症诱导的内皮细胞代谢重编程可以直接影响表观遗传修饰和细胞 功能和/或导致细胞记忆尚不清楚。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是由糖酵解增加介导的假设 和组蛋白乙酰化，随后可以导致持续的表观遗传特征。目标 1 将评估 使用各种代谢方法以 EC 特异性方式研究急性炎症对细胞功能的体内影响 表型分析和高通量测序方法，无论是否存在糖酵解 抑制剂。此外，将采用靶向空间转录组学来确定不同的贡献 炎症诱导的内皮功能障碍中的 EC 亚群。在目标 2 中，我们将使用以下方法进行体外测定： 人类 EC 进一步研究代谢重编程和表观遗传的分子机制 炎症条件下的修饰，并确定这些修饰是否可以保留和 导致细胞记忆。该项目获得的结果将为 EC（失调）功能提供有价值的见解， 并有潜力确定以代谢和/或表观遗传学为中心的治疗靶点 炎症相关疾病。