The Role of ARNT in Vascular and Cardiac Developnent

ARNT 在血管和心脏发育中的作用

• 批准号: 7218358
• 负责人: DIANA L RAMIREZ-BERGERON
• 金额: $ 5.71万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-09 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218358
• 关键词: angiogenesis; cardiogenesis; cell differentiation; cell line; cell migration; cell proliferation; embryo /fetus tissue /cell culture; embryonic stem cell; gene targeting; genetically modified animals; hematopoiesis; hypoxia; hypoxia inducible factor 1; laboratory mouse; mammalian embryology; mesenchyme; oxygen tension; protein structure function; transcription factor; vascular endothelium; yolk sac

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.

描述（由申请人提供）：该K01奖的目的是向少数族裔首席研究员提供深入的指导和研究培训，以便有效地过渡到独立的学术研究员。 候选人将从良好的，高度励志的赞助商和咨询委员会成员那里获得科学和职业指导。 过去，研究人员专注于造血发展。 拟议的研究将把她的研究重新定向到心血管发展和低氧生物学领域的新技能。 该提案基于西蒙博士的实验室的工作，包括造血和血管生成中的工作。 重要的缺氧转录介质的低氧诱导因子（HIF）家族的各种亚基的突变已有助于理解02张力在早期胚胎发育过程中的作用。 HIF异二聚体ARNT亚基的废除导致胚胎杀伤力在涂料后10.5天（DPC）与蛋黄，胎盘，心脏和血管缺陷。 该建议的目的是表征02在心血管发育中的作用，尤其是在内皮细胞中。 具体目的是1）确定缺氧如何影响内皮行为，2）检查AMT - / - 小鼠的胚内组织的造血和血管生成潜力，以及3）确定缺氧对心脏发育的影响。 实现这些特定目标将提供对介导心血管系统生长和分化所需的生物学反应的缺氧信号的理解。 此外，对细胞和分子对缺氧的反应的检查将为各种疾病状态提供重要的见解，包括肿瘤生长，糖尿病性视网膜病，前球，伤口愈合和缺血。此外，该提案的详细研究和教职员工委员会的高级指导将有助于指挥研究人员成为心血管生物学领域的领导者。