The Role of ARNT in Endothelial Cells

ARNT 在内皮细胞中的作用

基本信息

批准号：
8791917
负责人：
DIANA L RAMIREZ-BERGERON
金额：
$ 39.27万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791917
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 genetic approach 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

项目摘要

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.

项目概要/摘要缺氧诱导因子 (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以及产后病理过程中运行的表达程序，包括原则上，HIF 有助于重要的遗传程序。调节和控制血管生长缺乏 HIF 的小鼠表现出发育停滞。然而，HIF 规范的特定作用的意义。血管内皮细胞（EC）中的途径缺乏此方面的长期研究目标。应用的目的是确定 HIF 如何响应缺氧（低氧）环境来调节维持组织稳态所必需的血管生长已被证明具有特殊性。 HIF 的活性与细胞和环境相关，该提案提出了 EC-的一般假设。 HIF 激活不同的基因，在血管的各个阶段调节特定类型的血管生长我们将进一步确定 HIF 是否对 HIF 产生反应。缺氧，调节 VEGF 受体的时间表达，这对于介导特异性实验设计利用了 EC 中的信号，包括它们的存活、增殖和行为。 Arnt 条件（血管中的 HIF-¿ 必需亚基）小鼠遗传系统完全失活胚胎发育各个阶段以及成人 EC 中的 HIF 转录活性脉管系统能够在 EC 期间调查 HIF 的要求和作用血管的建立、成熟和维持以及对血管损伤的反应。具体目标 1 将研究胚胎发育关键阶段 EC 中 HIF 失活如何导致目标 2 解决了成人血管稳态中 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）。目标 3 将检查 EC 内 HIF 的内在要求，并检验 HIF 的假设部分通过调节 VEGF 受体的表达来促进 EC 存活。本文提出的目的是为了扩大我们对缺氧调节机制的理解正常和病理环境下的血管生成和稳态。