Consequences of Cell Death in Drosophila

描述(申请人提供)：电离辐射(IR)是癌症的主要治疗模块，因为它能够诱导细胞死亡。了解使细胞对IR杀伤或多或少敏感的机制是迈向更多放射治疗的关键的第一步 有效。这项提议的目标是理解一种这样的机制。具体地说，该提案将以果蝇为模型，探讨死亡细胞保护附近细胞免受IR诱导的凋亡的机制。初步研究已经发现了这一机制中的两个关键角色，一个是受体酪氨酸激酶(RTK)，一个是microRNA。这一资助期的目标是确定更多的分子成分，以便完全了解死亡细胞的这一新效应。其目的是：1.调查保护作用下的候选基因产物是死亡细胞还是受保护细胞所必需的；2.确定激活RTK的信号。3.在正向遗传筛查中确定信号通路的其余组成部分。该项目的影响将是通过对细胞死亡的新反应的分子理解来推动该领域的进步。另一个潜在的影响可能是在未来的研究中识别出临床相关的哺乳动物系统中的类似反应。如果保存在人类身上，死亡细胞使邻近细胞对IR更具抵抗力的机制可能具有深远的临床意义，特别是在放射治疗和细胞毒化疗相继应用的情况下。

DESCRIPTION (provided by applicant): Ionization radiation (IR) is a major treatment module for cancer because of its ability to induce cell death. Understanding mechanisms that make cells more or less sensitive to killing by IR is an essential first step towards making radiotherapy more effective. The goal of this proposal is to understand one such mechanism. Specifically, the proposal will address a mechanism by which dying cells protect nearby cells from IR-induced apoptosis, using Drosophila as a model. Preliminary studies have uncovered two key players in this mechanism, a receptor tyrosine kinase (RTK) and a microRNA. The goal of this funding period is to identify additional molecular components, in order to reach a complete understanding of this novel effect of dying cells. The Aims are: 1. Investigate whether candidate gene products that underlie the protective effect are required in dying cells or in protected cells 2. Identify the signal that activates the RTK. 3. Identify the remaining components of the signaling pathway in a forward genetic screen. The impact of this project will be the advancement of the field through a molecular understanding of a novel response to cell death. Another potential impact could be the identification of a similar response in clinically relevant mammalian systems in future studies. If conserved in human, a mechanism by which dying cells render nearby cells more resistant to IR could have profound clinical implications, especially in settings where radiotherapy is applied sequentially with cytotoxic chemotherapy.