Role of Piezo1-controlled Prox1 Modification in Lymphatic Valve Formation

PROGRAM SUMMARY Our proposal aims to elucidate how lymphatic endothelial cells detect external fluid forces and convert these signals into a biological program that orchestrates lymphatic valve formation. We are particularly focused on the role of Piezo1, a mechanosensitive ion channel in lymphatic endothelial cells, in sensing bidirectional oscillatory fluid flow and activating downstream effectors. This activation leads to a post-translational modification of Prox1, the homeodomain transcription factor critical for lymphatic development. We hypothesize that this specific modification of Prox1 is essential for the formation of lymphatic and lymphovenous valves, as the modification alters its transcriptional activity by affecting protein stability and binding affinity with partners. The primary goal of this project is to deepen our understanding of how Prox1 activity is influenced by mechanical stimuli and to understand the functional implications of these modifications in lymphatic valve development. Our approach will incorporate a range of methods including in vitro experiments, ex vivo assays, and innovative animal models, including mutant and transgenic mice, to test the central hypothesis. This research seeks to uncover the essential molecular mechanisms that control lymphatic development and may identify new therapeutic targets for treating lymphatic-related disorders. We anticipate that our findings will provide fresh insights into the molecular underpinnings of lymphatic anomalies and valve dysfunctions, potentially offering the development of targeted treatments for lymphatic malformations and other related vascular conditions.