Metabolic and epigenetic reprogramming in the inflamed endothelium

血管内皮细胞(ECs)在血液和底层组织之间形成一个动态的界面。与一致 它们在血管床上的特殊功能以及快速响应不同 (病理)生理刺激，内皮细胞既具有显著的异质性，又具有高度的代谢活性。 此外，鉴于内皮的战略位置，它在炎症中起着关键作用，而炎症是炎症的基础 许多人类疾病。最近的研究表明，炎症诱导的EC功能障碍与 代谢途径的改变，特别是糖酵解的增强。因此，细胞可以积累新陈代谢 乙酰辅酶A等中间体。除了它们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发挥重要作用，从而调节细胞功能。 虽然组蛋白修饰原则上是可逆的，但它们可以保留并导致细胞记忆。这 不仅对细胞类型鉴定很重要，而且在先天免疫中也起着重要作用。然而，无论是 炎症诱导的内皮细胞代谢重编程可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，这可以随后导致持续的表观遗传签名。目标1将评估 急性炎症对细胞功能的体内影响以EC特有的方式利用多种代谢 表型分型和高通量测序方法，在没有糖酵解和存在糖酵解的情况下 抑制剂。此外，将使用定向空间转录来确定不同的 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 人类内皮细胞将进一步研究代谢重编程和表观遗传学的分子机制 在炎症条件下的修改，并确定这些修改是否可以保留和 通向细胞记忆。本项目所获得的结果将对EC(Dys)的功能提供有价值的见解， 并有可能确定以代谢和/或表观遗传学为中心的治疗靶点 与炎症相关的疾病。

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.