MOLECULAR PHYSIOLOGY OF HYPOXIA INDUCED STRESS

缺氧引起的应激的分子生理学

• 批准号: 2837735
• 负责人: Amato J. Giaccia
• 金额: $ 20.48万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-15 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837735
• 关键词: RNase protection assay; SCID mouse; angiogenesis; apoptosis; biological signal transduction; enzyme activity; gene expression; gene mutation; genetic regulatory element; growth factor receptors; hypoxia; immunocytochemistry; neoplasm /cancer genetics; neoplastic process; northern blottings; oncogenes; phosphatidylinositol 3 kinase; physiologic stressor; platelet derived growth factor; receptor expression; tissue /cell culture; tumor necrosis factor alpha; tumor necrosis factor beta; vascular endothelial growth factors; western blottings

DESCRIPTION: Recent experimental studies have implicated tumor micro-environment in the selection of particular genetic mutations during tumorigenesis. In response to low oxygen conditions in the growing tumor mass, certain oncogenic mutations appear to predispose cells to apoptotic cell death. This leads to selection for anti-apoptotic mutations and for a genetic switch to a pro-angiogenesis phenotype. This switch to the angiogenic phenotype is associated with a coordinated increase in expression of angiogenic-promoting cytokines such as TNFalpha, bFGF, PDGF, and VEGF. Based on data that shows that oncogenic forms of Ha-Ras can increase the expression of VEGF, the hypothesis is put forth that oncogenic transformation primes cells for VEGF expression and that tumor hypoxia would then provide the necessary signal to increase or maintain the state of angiogenic growth factor production. Experiments are proposed which will: 1) Investigate whether cells which express oncogenic forms of Ras utilize PI-3 kinase in signaling the induction of pro-angiogenic cytokines and mitogens and whether this induction is regulated through HIF-1 and CACACAG/C; 2) To determine how Ras interacts with PDGF receptor and PI-3K signaling in the induction of VEGF; and 3) To investigate the relationship between the Ras and myc oncogenes and promoting cell death or survival at the unicellular and multicellular stages.

描述：最近的实验研究暗示了肿瘤 在选择特定遗传突变期间的微环境 肿瘤发生。 响应生长肿瘤中低氧条件 质量，某些致癌突变似乎易于细胞凋亡 细胞死亡。 这导致选择抗凋亡突变和 遗传切换到促血管生成表型。 此切换到 血管生成表型与表达的协调增加有关 血管生成促进细胞因子，例如TNFALPHA，BFGF，PDGF和VEGF。 基于数据表明，HA-RAS的致癌形式可以增加 VEGF的表达，假设是致癌的 转化素细胞为VEGF表达，肿瘤缺氧将 然后提供必要的信号以增加或保持状态 血管生长生长因子产生。 提出了实验，该实验将： 1）研究表达致癌形式的RAS的细胞是否利用 PI-3激酶在信号诱导前血管生成细胞因子和 有丝分裂剂以及该诱导是否通过HIF-1和 cacacag/c; 2）确定RAS如何与PDGF受体和PI-3K相互作用 VEGF诱导中的信号传导； 3）调查关系 在Ras和Myc Oncogenes之间，促进细胞死亡或生存 单细胞和多细胞阶段。