The Role of ARNT in Endothelial Cells

ARNT 在内皮细胞中的作用

• 批准号: 8207877
• 负责人: DIANA L RAMIREZ-BERGERON
• 金额: $ 39.57万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207877
• 关键词: ARNT gene; Address; Adult; Affect; Anatomy; Behavior; Biological; Blood Vessels; Cardiovascular system; Cell Hypoxia; Cell Proliferation; Cell Survival; Cells; Chemotaxis; Clinical; Data; Defect; Dependency; Development; Disease; Embryo; Embryonic Development; Endothelial Cells; Endothelium; Environment; Experimental Designs; Gene Expression; Generations; Genes; Genetic; Genetic Programming; Genetic Transcription; Growth; Hematopoietic; Homeostasis; Human; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Inducible Factor Pathway; Impairment; Injury; Investigation; Ischemia; Laboratories; Lead; Maintenance; Mediating; Molecular; Mus; Myocardium; Nutrient; Oxygen; Pathology; Pathway interactions; Phenotype; Physiological; Play; Pre-Eclampsia; Process; Production; Regulation; Research; Role; Signal Transduction; Staging; Stimulus; System; Testing; Therapeutic Agents; Tissues; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular remodeling; Work; Wound Healing; abstracting; angiogenesis; bHLH-PAS factor HLF; embryo tissue; human ARNT protein; hypoxia inducible factor 1; in vivo; innovation; insight; loss of function; migration; programs; response; sensor; skeletal; tissue regeneration; tissue repair; transcription factor; tumor; tumorigenesis; vasculogenesis

Project Summary/Abstract Hypoxia Inducible Factor (HIF) is a critical sensor of tissue O2 levels and governs angiogenic gene expression programs operating during embryogenesis as well as in post-natal pathologies including wound healing and ischemia. In principle, HIF contributes to important genetic programs responsible for moderating and controlling vascular growth. Mice deficient in HIF display developmental arrest due to multiple cardiovascular anomalies. However, the significance of a specific role for the HIF-canonical pathway in vascular endothelial cells (ECs) is lacking. The long-term research objective of this application is to determine how HIF, in response to the hypoxic (low oxygen) environment, regulates vascular growth necessary for maintaining tissue homeostasis. It has been demonstrated the specific activity of HIF is cell- and context- dependent. This proposal addresses the general hypothesis that EC- HIF activates distinct genes regulating specific types of vessel growth at various stages of vascular development and in post-natal angiogenesis. We will further determine whether HIF, in response to hypoxia, moderates the temporal expression of VEGF receptors that are important in mediating specific signals in ECs including their survival, proliferation, and behavior. The experimental design utilizes an Arnt-conditional (HIF-¿ obligatory subunit in vessels) mouse genetic system that completely inactivates HIF-transcriptional activity in ECs at various stages of embryonic development as well as in the adult vasculature enabling the investigations of HIF's requirement(s) and role(s) within ECs during the establishment, maturation, and maintenance of blood vessels as well as in response to vascular injury. Specific Aim 1 will examine how HIF inactivation in ECs at critical stages of embryonic development lead to specific angiogenic defects. Aim 2 addresses the requirement(s) for HIF in adult vessel homeostasis and various types of vascular responses (neoangiogenesis, angiogenesis, and arteriogenesis). Finally, Aim 3 will examine the intrinsic requirements of HIF within ECs and test the hypothesis that HIF is important in promoting EC survival in part by regulating the expression of VEGF receptors. The studies proposed herein intend to expand our understanding of the mechanisms by which hypoxia regulates vessel generation and homeostasis in both normal and pathological settings.

项目摘要/摘要 低氧诱导因子（HIF）是组织O2水平的关键传感器，并控制血管生成基因 在胚胎发生期间以及在产后病理中运行的表达程序 伤口愈合和缺血。原则上，HIF为负责的重要遗传计划做出了贡献 调节和控制血管生长。缺乏HIF的小鼠表现出由于 多个心血管异常。但是，特定作用对HIF-Canonical的重要性 缺乏血管内皮细胞（EC）的途径。这个长期研究目标 应用是确定HIF如何响应低氧（低氧）环境来调节 维持组织稳态所需的血管生长。已经证明了特定的 HIF的活性是细胞和上下文依赖性的。该提议解决了以下一般假设 HIF激活不同的基因，该基因在血管的各个阶段调节特定类型的血管生长 发育和产后血管生成。我们将进一步确定HIF是否回应 缺氧，调节VEGF受体的临时表达，这在介导特异性方面很重要 EC中的信号包括其生存，增殖和行为。实验设计利用 ARNT条件（血管中的HIF-强制性亚基）小鼠遗传系统，完全失活 在胚胎发育的各个阶段以及成年人的EC中的HIF转录活动 脉管系统可以调查HIF的需求和EC中的角色 血管的建立，成熟和维持以及响应血管损伤。 具体目标1将检查HIF如何在胚胎发育铅的关键阶段中的EC中失活 特定的血管生成缺陷。 AIM 2满足了成人船体体内稳态中HIF的要求 以及各种类型的血管反应（新血管生成，血管生成和动脉生成）。最后， AIM 3将检查ECS中HIF的内在要求，并检验HIF为 对于促进EC存活的重要性部分，部分通过调节VEGF受体的表达。研究 本文提出的意图是扩大我们对缺氧调节机制的理解 在正常和病理环境中，血管产生和体内平衡。