Consequences of Cell Death in Drosophila

描述（由申请人提供）：电离辐射（IR）是癌症的主要治疗模块，因为其能够诱导细胞死亡。了解使细胞对IR杀伤更敏感或更不敏感的机制是使放射治疗更有效的重要第一步。 有效本提案的目的是了解一种这样的机制。具体来说，该提案将以果蝇为模型，解决垂死细胞保护附近细胞免受IR诱导的凋亡的机制。初步研究发现了这一机制中的两个关键参与者，受体酪氨酸激酶（RTK）和microRNA。该资助期的目标是确定额外的分子组分，以便完全理解这种垂死细胞的新效应。目标是：1.调查是否候选基因产物的保护作用的基础是需要在垂死的细胞或受保护的细胞2。识别激活RTK的信号。 3.在正向遗传筛选中识别信号通路的其余组分。 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进该领域。另一个潜在影响可能是在未来的研究中确定临床相关哺乳动物系统中的类似反应。如果在人类中保守，死亡细胞使附近细胞对IR更具抗性的机制可能具有深远的临床意义，特别是在放射治疗与细胞毒性化疗顺序应用的情况下。

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.