Deciphering the transcriptional program that instructs lymphatic endothelial cell fate. (2016–2018)
Abstract:
The lymphatic vascular tree plays crucial roles in the drainage of lymph from interstitial spaces, in regionalized immune responses and in the transport of fatty acids and hormones. This network plays a critical role under pathological conditions such solid tumours and is central to elicit a metastatic response. Despite the discovery of the initial molecular switch that triggers the genetic program of lymphatic differentiation in venous endothelial cells, really little is known regarding how gene expression is coordinated by transcription factors to initiate and maintain lymphatic endothelial cell fate. This research proposal will address this gap in our knowledge by exploring at a molecular level how transcription factors instruct lymphatic endothelial cell specification. The specific project aims are as follows: AIM 1 ¿¿¿ To functionally characterize SOX18 dimer function that initiates LEC specification in vitro and in vivo. AIM 2 ¿¿¿ To identify and characterize key genomic regulatory elements important for LEC fate specification. AIM 3 ¿¿¿ To explore functional consequences of a series of allelic mutation in SOX18 that mediates a human lymphatic vascular disorder. OUTCOME: The research is significant because: 1) It will identify and characterise a SOX18 code of protein partners that drive lymphatic endothelial cell fate. 2) This project will reveal a hub of SOX18 target genes that orchestrate lymphangiogenesis. 3) More broadly this project will uncover pathways that can be potentially manipulated to target pathological vascular outgrowth such as tumour-induced neo-lymphangiogenesis
