CELL SITE SPECIFIC MICROBEAM IRRADIATION AND RESPONSES

描述：研究目标旨在了解 特定辐射损伤的识别与处理 强调染色体异常的形成。核DNA变化 与细胞死亡有明确的关系，显著影响人类健康， 突变和致癌改变。然而，目前还不确定 非核靶诱导的应力对Long的潜在贡献 有害影响一词。很明显，分子间的相互作用 膜、细胞质和细胞核参与损伤识别、信号传递 和反应路径。P53分子是牵涉其中的一个途径成分 在广泛的细胞控制反应中，在一种突变或废除的 形体与许多人类癌症有关。对……作用的理解 可以有效地获得辐射响应中的亚细胞成分 通过使用微光束。高LET电荷的定向光束粒子可以 在亚细胞微丸中启动显著水平的损害 单细胞显微镜检查可潜在定位基因产物/S 到这样的亚细胞区域。在本提案中，我们将使用小区站点 特定微束辐射提出的问题：可以无核吗 辐射引发染色体断裂反应或细胞周期延迟 以及P53的表达和定位。P53的动力学是什么？ 有什么反应？受辐射的细胞能否在未受辐射的情况下启动反应 邻里?(唯一可以用微束实现的)。人类起源的细胞， 正常和突变(ATM)以及表达野生型和突变型P53的细胞 将在这些研究中使用构造。基于染色体畸变率 形成动力学，假设P53不参与最初的 DNA损伤传感和修复，但它是一个监视组件，有助于 确保基因组的完整性。这些基于微束的研究将有助于 提供时空框架，用于识别和解析 辐射损伤和分子组成。

DESCRIPTION: Research objectives are directed toward understanding the recognition and processing of radiation induced lesions with a particular emphasis on the formation of chromosomal aberrations. Nuclear DNA changes significantly impact human health with clear relationships to cell death, mutation and oncogenic change. There is uncertainly however as to the potentia contributions of stresses induced in non-nuclear targets to long term deleterious effects. It is clear that molecular interplay between membrane, cytoplasm and nucleus contributes to damage recognition, signaling and respons pathways. The p53 molecule is one pathway component implicated in a broad rang of cellular control responses and in a mutated or abrogated form is involved i many human cancers. An understanding of the role of sub-cellular components in radiation responses can efficiently be obtained by use of a microbeam. A directed beam of high LET charges particles can initiate significant levels of damage in sub-cellular microbolumes and single cell microscopic examination ca potentially localize gene product/s to such sub-cellular regions. In this proposal we will use cell site specific microbeam irradiation to ask the questions: Can non-nuclear irradiation initiate chromosomal clastogenic responses or cell cycle delay and p53 expression and localization. What is the kinetics of a p53 response? Can irradiated cells initiate responses in unirradiated neighbors? (uniquely achievable with a microbeam). Cells of human origin, normal and mutant (ATM), and cells expressing wild type and mutant p53 constructs will be used in these studies. Based on chromosomal aberration formation kinetics, it is hypothesized that p53 is not involved in initial DNA damage sensing and repair but is a surveillance component that helps to ensure genomic integrity. These microbeam based studies will help to provide a spatio-temporal framework for the recognition and resolution of radiation induced damage and the molecular components.