TGFBeta signaling pathway in arterial cell fate regulation

项目总结/摘要 拟议的研究计划的目标是研究如何组成我们的血管内皮细胞被分配动脉的命运，从而构成动脉血管系统，与静脉和淋巴系统平行。由于动静脉命运的失调可能导致无数的血管疾病，这项工作的目的是了解动脉的身份是如何获得，调节和维持的。这项工作将阐明动脉特化计划期间转录控制的新调控途径，并将为血管疾病提供新的潜在治疗靶点。该提案是一项为期五年的职业发展计划，旨在为卡洛斯利扎马博士从事独立的科学学术生涯做好准备，研究动脉规格计划的生物学和调节。该项目将建立在Lizama博士在血管发育方面的背景之上，同时将他的研究技能扩展到转录调控和蛋白质-DNA相互作用的新途径。该培训计划将在Lizama博士的共同导师Ann Zovein博士和Dean Sheppard博士的指导下进行，他们将监督他的科学进步，同时为他向独立职业的过渡做好准备。该提案将使Lizama博士能够发展他的独立研究方向，重点是了解控制动脉规格和维护的信号通路。前期工作已经确定了TGFβ1通路在控制动脉特性中的重要作用。Lizama博士将对他的初步观察结果进行随访，并检验TGFβ超家族在动脉特化以及生血内皮细胞的造血开关中发挥不可或缺的作用的假设。他将确定是否存在将TGFβ通路与动脉命运的SoxF转录调节因子连接起来的转录蛋白复合物。拟议的计划将提供对血管生物学的重要见解，同时将Lizama博士转变为独立的教师职位，并建立他在动脉基因调控方面的独特研究计划。

Project Summary/Abstract 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 TGFβ1 pathway in controlling the arterial identity. Dr. Lizama will follow up on his initial observations and test the hypothesis that the TGFβ 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 TGFβ 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.