HYPOXIC STRESS MECHANISMS IN RADIATION AND CHEMOTHERAPY

放射治疗和化疗中的缺氧应激机制

• 批准号: 6921532
• 负责人: BRIAN J MURPHY
• 金额: $ 33.91万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-12 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6921532
• 关键词: antineoplastics; biological signal transduction; cesium; drug resistance; hypoxia; intracellular transport; laboratory mouse; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer radiation therapy; neoplasm /cancer transplantation; neoplastic process; oxidation reduction reaction; phosphorylation; radiation resistance; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The metal transcription factor-1 (MTF-1) is a metal and redox-sensitive protein that is essential for embryonic development and involved in the transcriptional regulation of a growing number of tumor-related proteins including metallothionein, placenta growth factor, zinc transporter-1, glucose-6-phosphate, dehydrogenase, and matrix metalloproteinases. This laboratory has found MTF-1 to be highly expressed in human carcinomas and to be positively associated with the metastatic potential of human breast cancer cell lines. The genetic loss of MTF-1 results in suppression of experimental tumor growth and angiogenesis through enhanced deposition of extra-cellular matrix, caused in part by increased expression and activation of the transforming growth factor-pi and tissue transglutaminase, and attenuated expression of some matrix metalloproteinases. This group has also found MTF-1 to be involved in chemo- and radio-resistance, to contribute to the accumulation of the hypoxia-inducible factor-1 a (HIF-la) in response to hypoxia, and to be implicated in hypoxia-inducible signaling through two central mitogen activated protein kinase pathways. The first set of studies (Specific Aim 1) will address the putative role of MTF-1 in conferring chemo- and radio-resistance and translational relevance using human xenografts. It will also assess downstream contributions from HIF-la, and other specific signaling pathways. Aim 2 will define the underlying molecular mechanisms involved hi the regulation of HEF-la accumulation by MTF-1. An understanding of this regulatory pathway is important since HIF-la is believed to play a key role in tumorigenesis, angiogenesis and therapy resistance. Aim 3 will address the interaction between tumor and host cells in the initiation and progression of tumor growth as a function of MTF-1 expression utilizing MTF-1 conditional knockout mice and conditional knockout cell lines. The relative roles of MTF-1 and HIF-la in angiogenesis and initiation of tumor development, using the novel dorsal skin flap window chamber model, will also be addressed. An understanding of these MTF-1-dependent properties should aid in the development of novel prognostic and new modalities for neoplastic diseases.

描述（由申请人提供）：金属转录因子-1（MTF-1）是一种金属和氧化还原敏感蛋白，对于胚胎发育至关重要，并参与越来越多的肿瘤相关蛋白的转录调节，包括金属硫蛋白、胎盘生长因子、锌转运蛋白 1、葡萄糖-6-磷酸、脱氢酶和基质金属蛋白酶。 该实验室发现MTF-1在人类癌症中高表达，并且与人类乳腺癌细胞系的转移潜力呈正相关。 MTF-1的遗传缺失导致细胞外基质沉积增强，从而抑制实验性肿瘤生长和血管生成，部分原因是转化生长因子-pi和组织转谷氨酰胺酶的表达和激活增加，以及某些基质的表达减弱金属蛋白酶。该小组还发现 MTF-1 参与化疗和放射抗性，有助于响应缺氧而积聚缺氧诱导因子 1a (HIF-1a)，并与缺氧有关。通过两个中央有丝分裂原激活蛋白激酶途径的诱导信号传导。 第一组研究（具体目标 1）将探讨 MTF-1 在使用人类异种移植物赋予化疗和放射抗性以及转化相关性方面的假定作用。 它还将评估 HIF-1α 和其他特定信号通路的下游贡献。 目标2将定义涉及MTF-1调节HEF-1α积累的潜在分子机制。 了解该调节途径非常重要，因为 HIF-1α 被认为在肿瘤发生、血管生成和治疗抵抗中发挥关键作用。 目标 3 将利用 MTF-1 条件敲除小鼠和条件敲除细胞系，解决肿瘤生长起始和进展中肿瘤与宿主细胞之间的相互作用，作为 MTF-1 表达的函数。 还将使用新型背侧皮瓣窗室模型来探讨MTF-1和HIF-1a在血管生成和肿瘤发展起始中的相对作用。 了解这些 MTF-1 依赖性特性应有助于开发肿瘤疾病的新预后和新模式。