HIF- 2ALPHA, Hypoxic Gene Regulation, and Angiogenesis

HIF-2ALPHA、缺氧基因调节和血管生成

• 批准号: 8286244
• 负责人: M. CELESTE SIMON
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286244
• 关键词: ARNT gene; Ablation; Adult; Affect; Astrocytoma; Attention; Binding; Blood Vessels; Bone Marrow; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Colon Carcinoma; Complex; Conventional (Clear Cell) Renal Cell Carcinoma; Defect; Development; Disease; Embryo; Endothelial Cells; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Glycolysis; Goals; Growth; Hematopoiesis; Hypoxia; Hypoxia Inducible Factor; In Vitro; Ischemia; Life; Limb structure; Malignant Neoplasms; Mediating; Modeling; Molecular; Morphology; Mus; Myocardial Infarction; Neuroblastoma; Oxygen; Pathologic Neovascularization; Patients; Perinatal; Phenotype; Physiological; Physiology; Play; Primary carcinoma of the liver cells; Process; Proteins; Reporting; Role; Signal Transduction; Solid Neoplasm; Stroke; Testing; Tissues; Transgenes; Tube; Tumor Angiogenesis; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular remodeling; adrenomedullin; alveolar type II cell; angiogenesis; bHLH-PAS factor HLF; cell motility; cell type; deprivation; design; gene induction; hypoxia inducible factor 1; in vivo; insight; lung small cell carcinoma; macrophage; migration; monocyte; neovascularization; new therapeutic target; outcome forecast; postnatal; research study; response; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Cellular responses to changes in available oxygen (O2) levels are essential for normal development and physiology, and play a crucial role in disease. Hypoxia-inducible factors (HIFs) participate in these responses by stimulating the expression of genes involved in glycolysis, hematopoiesis, cell motility, and angiogenesis, all of which contribute to hypoxic adaptations. HIFs are heterodimeric transcription factors consisting of 1 (HIF-11 or HIF-21) and 2 (ARNT) subunits. Much attention has been focused on the ubiquitously expressed HIF-11 factor. However, the related protein HIF-21 clearly plays an important, as yet largely undetermined role in hypoxic adaptations. HIF-21 is highly expressed in endothelial cells (ECs) and regulates the expression of multiple genes that control angiogenesis such as VEGF, Tie2, and adrenomedullin. Moreover, HIF-21 preferentially regulates hypoxic VEGF expression in multiple cell types. Previous reports describe the effects of ablating HIF-11 in ECs, while little is known about HIF-21 function in these cells. To fully understand the complex role of hypoxia in controlling angiogenesis, particularly in response to pathological conditions such as tissue ischemia and solid tumors, it is important to establish the mechanisms by which HIF-21 functions in ECs and proangiogenic bone marrow-derived cells. This proposal will test the following hypothesis: HIF-21 plays critical and unique roles in regulating angiogenic responses to hypoxia, particularly during adult neovascularization. To test this hypothesis, we will (1) determine the role of HIF-21 in vascular EC function in vitro, (2) define the role of HIF-21 in ECs in vivo, and (3) determine the effects of HIF-21 ablation in the recruitment and function of proangiogenic bone marrow derived-monocytes (BMDMs). The proposed experiments are timely, in that recent reports suggest that HIF-21 (but not HIF-11) is critical to the progression of specific malignancies such as renal clear cell carcinoma, small cell lung carcinoma, neuroblastoma, and astrocytoma. The overall goal of these studies is to delineate how HIF-11 and HIF-21 differentially regulate hypoxic gene induction and how this contributes to angiogenesis, especially in adult pathophysiological settings. Project Narrative:Oxygen is essential for most life forms on earth. Therefore, responses to changes in oxygen availability are critical for development, physiology, and diseases such as the growth of solid tumors or tissue ischemia. Oxygen sensitive hypoxia-inducible factors participate in these responses and have been implicated in the growth of tumors such as renal clear cell carcinoma, small cell lung carcinoma, colon carcinoma, and neuroblastoma. This project will provide fundamental insights into how these factors regulate blood vessel growth in diseases and identify new therapeutic targets to treat cancer, stroke, and heart attack patients.

描述（由申请人提供）：细胞对可用氧气变化（O2）水平的反应对于正常发育和生理学至关重要，并且在疾病中起着至关重要的作用。低氧诱导因子（HIF）通过刺激参与糖酵解，造血，细胞运动性和血管生成的基因的表达来参与这些反应，所有这些都会导致低氧适应。 HIF是由1（HIF-11或HIF-21）和2（ARNT）亚基组成的异二聚体转录因子。非常关注无处不在表达的HIF-11因子。但是，相关的蛋白质HIF-21显然在低氧适应中起着重要的作用，但在很大程度上尚不确定。 HIF-21在内皮细胞（EC）中高度表达，并调节控制诸如VEGF，TIE2和肾上腺素蛋白等血管生成的多个基因的表达。此外，HIF-21优先调节多种细胞类型中的低氧VEGF表达。先前的报道描述了消融HIF-11在EC中的影响，而对这些细胞中的HIF-21功能知之甚少。为了充分了解缺氧在控制血管生成中的复杂作用，特别是在对病理状况（例如组织缺血和实体瘤）的反应中，重要的是建立HIF-21在ECS和促骨骨髓衍生的细胞中起作用的机制。该提案将检验以下假设：HIF-21在调节对缺氧的血管生成反应中起关键和独特的作用，尤其是在成人新血管形成期间。为了检验这一假设，我们将（1）确定HIF-21在体外血管EC功能中的作用，（2）定义HIF-21在体内ECS中的作用，（3）确定HIF-21消融在募集中的影响在招募和亲核骨骨髓衍生的环的招聘和功能中的作用。提出的实验是及时的，因为最近的报道表明，HIF-21（但不是HIF-11）对于特定恶性肿瘤的发展至关重要，例如肾脏透明细胞癌，小细胞肺癌，神经母细胞瘤和星形胶质细胞瘤至关重要。这些研究的总体目的是描述HIF-11和HIF-21如何差异调节低氧基因诱导以及这如何促进血管生成，尤其是在成人病理生理环境中。 项目叙述：氧气对于地球上的大多数生命形式都是必不可少的。因此，对氧气可用性变化的反应对于发育，生理和诸如实体瘤或组织缺血的生长等疾病至关重要。氧气敏感的缺氧诱导因子参与了这些反应，并与肿瘤的生长有关，例如肾透明细胞癌，小细胞肺癌，结肠癌和神经母细胞瘤。该项目将对这些因素如何调节疾病中的血管生长并确定治疗癌症，中风和心脏病发作患者的新治疗靶点的基本见解。