Regulation of Vascular Inflammation by Selectin Antagonists and Transcription Factor GATA5

Abstract

Chronic inflammation is a complex immune response linked to several diseases. The first step in the inflammatory response is the recruitment of immune cells to the endothelium of the vascular wall. This process is mediated by E/P-Selectin, for which no antagonist efficiently interacts to limit the inflammatory response. Previous work identified transcription factor GATA5 as a key regulator of endothelial homeostasis and revealed an altered expression of inflammatory genes in human endothelial cells with loss of GATA5. The objective of my project is to understand the role of GATA5 in selectin-dependent vascular inflammation and to develop selectin inhibitors. I used biochemical, cellular and in vivo approaches to evaluate a series of novel small molecules for their ability to interfere with selectin binding to their ligand, PSGL-1. The work identified a new lead candidate, LCB 2248, for the development of new E/P-Selectin antagonists and contributed to the understanding of the role of GATA5 in cell recruitment and adhesion. The mechanistic insight gathered and the identification of an E/P-Selectin antagonist will hopefully pave the way for the development of effective treatments for patients with chronic inflammation.