The goal of the proposed research program is to investigate how the endothelial cells that comprise our vasculature are assigned arterial fate, and thus constitute the arterial vascular system, in parallel with the venous and lymphatic systems. As de-regulation of arteriovenous fate can result in a myriad of vascular disorders, the work aims to understand how arterial identity is acquired, regulated, and maintained. The work will elucidate novel regulatory pathways of transcriptional control during the arterial specification program, and it will allow new potential therapeutic targets for vascular disorders. This proposal is for a five-year career development program designed to prepare Dr. Carlos Lizama for an independent scientific academic career studying the biology and regulation of the arterial specification program. The project will build on Dr. Lizama's background in hematovascular development, while expanding his research skills into new avenues of transcriptional regulation and protein-DNA interactions. The training program will take place under the guidance of Dr. Lizama's co-mentors Drs. Ann Zovein and Dean Sheppard who will oversee his scientific progress while preparing him for the transition to an independent career. The proposal will allow Dr. Lizama to develop his independent line of research focused on understanding the signaling pathways that control arterial specification and maintenance. The preliminary work has identified an important role for the TGF?1 pathway in controlling the arterial identity. Dr. Lizama will follow up on his initial observations and test the hypothesis that the TGF? superfamily plays an integral role in arterial specification, as well as in the hematopoietic switch in hemogenic endothelium. He will determine the existence of transcriptional protein complexes that connect the TGF? pathway to the SoxF transcriptional regulators of arterial fate. The proposed program will provide critical insights into vascular biology while transitioning Dr. Lizama to an independent faculty position and establishing his unique research program in arterial gene regulation.
Defects in the correct assignment of arterial and venous fate during development, or postnatal neo-vascularization is a root cause of human arterial-venous malformations. Elucidation of the mechanistic determinants of blood vessel specification will allow for potential new therapeutic targets for vascular disorders. The goal of this proposal is to define the major arterial identity signaling pathways and their role in proper vascular development and maintenance.
