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HEAT AND RADIATION INDUCED CHANGES IN THE NUCLEAR MATRIX

热和辐射引起的核基质变化

基本信息

批准号：
6172603
负责人：
JOSEPH R DYNLACHT
金额：
$ 11.11万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-05-01 至 2002-04-30
项目状态：
已结题

项目摘要

The nuclear matrix is important for defining nuclear structure and regulating metabolic processes such as DNA and RNA synthesis, and possibly DNA repair. We propose to determine whether the nuclear matrix is a critical structure involved in the manifestation of thermal damage and heat-radiosensitization. We will test the hypotheses that alterations in nuclear matrix proteins are related to heat-induced alterations in (or recovery of) nuclear matrix structure are correlated with cytotoxicity. Using antibodies against specific nucleic matrix proteins, we will quantitate heat-induced changes in nuclear lamin and interior matrix proteins, we will quantitate heat-induced changes in nuclear lamina nd interior matrix proteins, we will quantitate heat-induced changes in nuclear lamin and interior matrix proteins in situ using flow cytometry to determine the relative abundance of these proteins throughout the cell cycle. Structural changes in fixed cells will be evaluated with confocal microscopy and correlated with change in chromatin distribution and survival. Since changes ina the nuclear matrix might be expected to contribute to inhibition of DNA strand break repair observed during heat- radiosensitization, we will also determine temporal and spatial patterns of DNA repair in heated, irradiated cells. Flow cytometric quantitation of changes in nuclear matrix proteins may have clinical relevance as a predictive assay for response to anticancer treatments such as hyperthermia, since our preliminary data suggests that heat causes solubilization of lamin B in apoptotic an necrotic cells within hours after heating. Solubilization of nuclear matrix proteins could prove to be a rapid alternative to colony-forming assays for predicting heat sensitivity. Elucidation of the mechanisms of action of hyperthermia, alone or combined with radiation, may lead to optimization of cancer treatments and the preferential eradication of tumor cells.

核基质对于定义核结构和调节代谢过程，如DNA和RNA合成， DNA修复我们建议确定核基质是否是一种参与热损伤表现的关键结构，热辐射增敏。我们将测试假设，核基质蛋白与热诱导的改变有关（或核基质结构的恢复与细胞毒性相关。使用针对特定核基质蛋白的抗体，我们将定量核纤层蛋白和内部基质的热诱导变化蛋白质，我们将定量热诱导的变化，核纤层，内部基质蛋白，我们将定量热诱导的变化，核纤层蛋白和内部基质蛋白原位使用流式细胞术，确定这些蛋白质在整个细胞中的相对丰度周期将使用共聚焦显微镜评价固定细胞的结构变化。与染色质分布的变化相关，生存由于核基质中的变化可能会有助于抑制在加热过程中观察到的DNA链断裂修复，放射增敏，我们还将确定时间和空间模式， DNA修复在加热，辐射细胞。流式细胞术定量核基质蛋白的变化可能具有临床相关性，用于对抗癌治疗的反应的预测测定，因为我们的初步数据表明，核纤层蛋白B在凋亡和坏死细胞中溶解暖气核基质蛋白的溶解可以被证明是一种快速替代菌落形成试验预测热敏感性。阐明单独或联合高温的作用机制与辐射，可能会导致癌症治疗的优化和优先根除肿瘤细胞。