Epigenetic alterations in endothelial cells during sepsis and inflammation. New insights in sepsis-associated endothelial dysfunction?

van Midden, Wouter (2020) Epigenetic alterations in endothelial cells during sepsis and inflammation. New insights in sepsis-associated endothelial dysfunction? Master's Thesis / Essay, Biomedical Sciences.

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Abstract

Due to an excessive inflammatory response induced by the bacterial gram-negative compound LPS, the endothelial barrier integrity is disrupted in sepsis patients. Enhanced vascular permeability and thereby tissue leakage, can lead to multiple organ failure. Both genetic and epigenetic alterations underlie this endothelial dysfunction. Sepsis studies related to epigenetic alterations mainly focus on macrophages or monocytes, but the role of endothelial cells (ECs) is often not included. This thesis aimed to generate a broader perspective about the epigenetic alterations in ECs underlying endothelial dysfunction. Therefore, we will combine the current knowledge of both epigenetic alterations in ECs after inflammation, disturbed blood flow, and sepsis. Genes that are epigenetically altered can be divided into three groups: adhesion molecules, inflammatory cytokines, and genes associated with endothelial function. Of the last group, KLF2, Ang1, and VEGFR are promising therapeutic targets, as they regulate multiple downstream genes and endothelial integrity. Since several genes are regulated by both histone modifications and DNA methylation, combined treatment is necessary to increase the effect of the epigenetic inhibitors. A new system, CRISPR/dCas9, has shown to alter the epigenetic state in a highly specific way, thereby improving diseases like acute kidney injury (AKI) in vivo. Applications of this system could be used to target the aforementioned genes to restore endothelial

Item Type:	Thesis (Master's Thesis / Essay)
Supervisor name:	Rots, M.G.
Degree programme:	Biomedical Sciences
Thesis type:	Master's Thesis / Essay
Language:	English
Date Deposited:	17 Jan 2020 09:57
Last Modified:	17 Jan 2020 09:57
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/21415

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