NUCLEAR DETERMINANTS OF THERAPEUTIC RESPONSE

拟议研究计划的总体目标是测试 假设可测量的核成分参与了反应- (S)从哺乳动物细胞到治疗剂(电离辐射、超 热疗、化疗药物等)。一个充分的条件，足以- 支持这一假设的是原子核包含一个或多个可测量的 对给定治疗方式的反应的决定因素。如果这个条件- 如果是真的，那么这些可测量的决定因素就会 是潜在的临床相关预测分析的候选对象 治疗反应。因此，我们提出了一系列研究 调查特定核(和)之间关系的项目 相关的细胞质)成分和某些特定的细胞效应 治疗剂。这些包括与细胞相关的核决定因素 暴露于电离辐射或辐射后的死亡和/或损伤修复 体温过高与细胞增殖和细胞周期进程的决定因素 西翁。重点放在电离辐射和热疗上，因为 这些模式用于临床，不受膜的限制。细胞 在逻辑上将扩散包括在内，因为高温、电离辐射- TION和某些化疗药物引起细胞周期紊乱 这会导致不平衡的增长，进而会影响对 进一步治疗。在项目1中，一种特定的核基质蛋白将是 研究了它在锚定DNA环和辐射敏感性方面的作用- Y，这将提供对修复和固定的机制(S)的洞察 辐射损伤的可能性。在项目2中， 核基质和细胞骨架将从以下方面进行研究 细胞对辐射的敏感性。项目3建议的工作将是研究 胞核与胞浆之间的关系对血管内皮细胞生长因子表达的影响 体温过高后的致命损害。与项目3相比，项目3将是 在肿瘤细胞(体外和体内)上完成的，项目4将研究 高温对正常细胞系统--巨噬细胞系统的影响。 具体地说，项目4将调查环境因素的作用 巨噬细胞对高温的反应。这个系统将允许我们 寻找慢性热耐受诱导的决定因素。在……里面 项目5，细胞质和核蛋白与 受扰的细胞周期传递将被研究。在这个项目中，我们建议 寻找由不平衡导致的加速的G1过渡的决定因素 成长。

The overall objective of the proposed research program is to test the hypothesis that measurable nuclear components are involved in the response- (s) of mammalian cells to therapeutic agents (ionizing radiation, hyper- thermia,,chemotherapeutic drugs, etc.). A condition sufficient to substan- tiate this hypothesis is that nuclei contain one or more measurable determinants of response to a given therapeutic modality. If this condi- tion is true, then it would follow that such measurable determinants would be candidates for potential clinically relevant predictive assays for therapeutic response. Therefore, we are proposing a series of research projects to investigate the relationships between specific nuclear (and related cytoplasmic) components and given cellular effects of certain therapeutic agents. These include nuclear determinants related to cell killing and/or damage repair following exposure to ionizing radiation or hyperthermia and determinants of cell proliferation and cell-cycle progres- sion. Emphasis is placed on ionizing radiation and hyperthermia because these modalities are used clinically and are not membrane limited. Cell proliferation is included logically because hyperthermia, ionizing radia- tion and certain chemotherapeutic agents induce cell-cycle perturbations that result in unbalanced growth, which in turn can affect the response to further treatment. In Project 1, a specific nuclear matrix protein will be studied in terms of its role in anchoring DNA loops and in radiosensitivit- y, which will provide insight into the mechanism(s) of repair and fixation of radiation damage. In Project 2, the interrelationship between the nuclear matrix and the cytoskeleton will be investigated in terms of cellular radiosensitivity. Work proposed in Project 3 will be to study the relationship between the nucleus and cytoplasm affecting the expression of lethal damage after hyperthermia. In contrast to Project 3, which will be done on tumor cells (in vitro and in vivo), Project 4 will investigate the effects of hyperthermia on a normal cell system, the macrophage system. Specifically, Project 4 will investigate the role of environmental factors in the responses of macrophages to hyperthermia. This system will allow us to find determinants for the induction of chronic thermotolerance. In Project 5, the relationship between cytoplasmic and nuclear proteins and perturbed cell-cycle transit will be studied. In this project we propose to find determinants of accelerated G1 transit resulting from unbalanced growth.