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: 6758595
• 负责人: DIANA L RAMIREZ-BERGERON
• 金额: $ 13.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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/6758595
• 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(申请人提供)：这个K01奖项的目标是为少数族裔首席研究员提供密集的指导和研究培训，使他们能够有效地过渡到独立的学术研究人员。候选人将接受来自成熟的、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，这位研究人员一直专注于造血发展。这项拟议的研究将把她的研究转向在心血管发育和低氧生物学领域获得新技能。这项建议是基于西蒙博士的实验室所做的工作，包括造血和血管生成方面的工作。缺氧诱导因子(HIF)家族是一种重要的缺氧性转录调节因子，其多个亚基的突变有助于理解02张力在早期胚胎发育中的作用。去除HIF异源二聚体的ArnT亚单位导致胚胎在性交后10.5天内死亡，并伴有卵黄囊、胎盘、心脏和血管缺陷。这项提议的目的是描述02在心血管发育中的作用，特别是对内皮细胞的作用。其具体目的是1)确定低氧如何影响血管内皮细胞的行为，2)检测AMT-/-小鼠胚胎内组织的造血和血管生成潜力，以及3)确定低氧对心脏发育的影响。实现这些特定的目标将有助于了解低氧信号在调节心血管系统生长和分化所需的生物反应中的作用。此外，对缺氧的细胞和分子反应的检查将提供对各种疾病状态的重要见解，包括肿瘤生长、糖尿病视网膜病变、先兆子痫、伤口愈合和缺血。此外，对这项建议的详细研究和教员委员会的高级指导将有助于指挥调查员成为心血管生物学领域的领导者。