The Role of ARNT in Vascular and Cardiac Developnent

描述（由申请人提供）：这个K01奖项的目的是为少数族裔首席研究员提供强化指导和研究培训，使其能够有效地过渡到独立的学术研究人员。候选人将获得来自知名的、高度激励的赞助商和咨询委员会成员的科学和职业指导。过去，研究者主要关注造血发育。拟议的研究将使她的研究转向获得心血管发育和缺氧生物学领域的新技能。该提案是基于西蒙博士实验室的工作，包括造血和血管生成的工作。缺氧诱导因子（HIF）家族是一种重要的缺氧转录介质，其不同亚基的突变有助于理解02张力在早期胚胎发育中所起的作用。去除HIF异源二聚体的Arnt亚基导致胚胎在性交后10.5天死亡，并伴有卵黄囊、胎盘、心脏和血管缺陷。这项提议的目的是表征02在心血管发育中的作用，特别是在内皮细胞上。具体目的是1)确定缺氧如何影响内皮行为，2)检查Amt -/-小鼠胚胎内组织的造血和血管生成潜能，以及3)确定缺氧对心脏发育的影响。完成这些特定的目标将有助于理解缺氧信号在介导心血管系统生长和分化所需的生物反应中的作用。此外，检查细胞和分子对缺氧的反应将为各种疾病状态提供重要的见解，包括肿瘤生长、糖尿病视网膜病变、子痫前期、伤口愈合和缺血。此外，该提案的详细研究和教委的高级指导将有助于指挥研究者成为心血管生物学领域的领导者。

DESCRIPTION (provided by applicant): The objective of this K01 award is to provide intensive mentoring and research training to the minority principal investigator that will allow for an effective transition into an independent academic researcher. The candidate will receive scientific and career mentorship from well established, highly motivational sponsors and advisory committee members. In the past, the investigator has focused on hematopoietic development. The proposed research will redirect her research to acquisiton of new skills in the areas of cardiovascular development and hypoxic biology. The proposal is based on work from Dr. Simon's laboratory encompassing work in hematopoiesis and vasculogenesis. Mutations in various subunits of the Hypoxia Inducible Factor (HIF) family, an important hypoxic transcriptional mediator, have contributed to the understanding the role 02 tension plays during early embryonic development. Abrogation of the Arnt subunit of the HIF heterodimer resulted in embryonic lethality by 10.5 days postcoitum (dpc) with yolk sac, placental, cardiac, and vascular defects. The goal of this proposal is to characterize the role of 02 in cardiovascular development, particularly on endothelial cells. The specific aims are to 1) determine how hypoxia influences endothelial behavior, 2) examine the hematopoietic and angiogenic potential of intraembryonic tissues of Amt -/- mice, and 3) determine the effect of hypoxia in heart development. Accomplishing these specific aims will provide an understanding of hypoxic signals in mediating biological responses required for the growth and differentiation of the cardiovascular system. Furthermore, the examination of the cellular and molecular responses to hypoxia will provide important insights into various disease states, including tumor growth, diabetic retinopathy, preeclampsia, wound healing, and ischemia. Additionally, the detailed studies of this proposal and the senior guidance of the faculty committee will assist in commanding the investigator into a leader in the field of cardiovascular biology.