Metabolic and epigenetic reprogramming in the inflamed endothelium

内皮细胞（EC）在血液和下层组织之间形成动态界面。符合 它们跨血管床的专门功能和快速响应不同的 （病理）生理刺激，EC都是显着异质性和高度代谢活性。 此外，鉴于其战略位置，内皮细胞在炎症中起关键作用，这是炎症的基础。 许多人类疾病。最近的研究表明，炎症诱导的EC功能障碍与 代谢途径的变化，特别是糖酵解的增强。因此，细胞可以积累代谢产物， 中间体如乙酰辅酶A。除了它们在代谢中的已知作用之外，这些代谢物还 重要的是介导表观遗传过程，如组蛋白乙酰化，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 不仅对细胞类型的身份很重要，而且在先天免疫中也起作用。但无论 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凋亡。 功能，和/或导致细胞记忆，是未知的。因此，本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，这可能随后导致持续的表观遗传特征。目标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 表型和高通量测序方法，无论是在糖酵解的存在和不存在 抑制剂.此外，将采用靶向空间转录组学来确定不同基因的贡献。 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 人类内皮细胞，以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， 导致细胞记忆。本研究的结果将为EC（dys）功能提供有价值的见解， 并且具有鉴定以代谢和/或表观遗传为中心的治疗的治疗靶点的潜力， 炎症相关疾病。

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.