Determining cellular processes underlying apoptosis-induced cell proliferation through kinase analysis

细胞死亡和出生之间的平衡对包括人类在内的多细胞生物体的健康至关重要。破坏这种平衡可能会导致许多疾病，包括癌症和退行性疾病。因此，重要的是要了解细胞死亡和出生是如何协调的。我们和其他人最近的研究发现，死亡细胞发起了一种意想不到的交流。死亡细胞发出的信号会触发相邻细胞分裂并产生新的细胞，以弥补细胞的损失。这一过程被称为凋亡诱导的增殖(AIP)。然而，AIP是如何在分子水平上被激活和调节的，目前还不清楚。本研究旨在加深我们对AIP的理解。为此，我们选择果蝇这一强大的模式生物来研究体内介导细胞通讯的调控基因网络。我们已经在果蝇身上开发了独特的检测方法，使用组织过度生长或组织再生作为AIP的灵敏读数。这些读数允许快速识别和分析新型AIP调节器。通过这些分析，我们发现了26个新的AIP调控基因。这些基因的功能揭示了AIP背后的两个关键细胞过程。一个过程是细胞骨架的重塑，即细胞支架，而另一个过程被称为自噬，这是维持细胞内能量平衡的关键过程。拟议的工作是确定这些关键的细胞过程和其他已确定的新调节因子在调节AIP中的作用。这项研究的结果将帮助我们理解濒临死亡的细胞是如何与邻近细胞对话来诱导细胞替换的。由于AIP与包括人类在内的哺乳动物的再生(组织修复)和肿瘤生长(癌症)有关，拟议的工作可以为再生医学和癌症治疗提供潜在的药物靶点。

A balance between cell death and birth is critical for health of multi-cellular organisms including humans. Disruption of such a balance can lead to many diseases including cancer and degenerative disorders. It is therefore important to understand how cell death and birth are coordinated. Recent work by us and others discovered an unexpected communication initiated from dying cells. Signals emitted from dying cells trigger their neighbouring cells to divide and generate new cells which can compensate for the cell loss. This process is termed Apoptosis-induced Proliferation (AiP). However, it remains elusive how AiP is activated and regulated at the molecular level. The proposed research aims to advance our understanding of AiP. For this purpose, we chose the fruit-fly Drosophila which is a powerful model organism to investigate the regulatory gene network that mediates cellular communication in vivo. We have developed unique assays in Drosophila using either tissue overgrowth or tissue regeneration as sensitive readouts of AiP. These readouts allow quick identification and analysis of novel AiP regulators. By employing these assays we have identified 26 new regulatory genes of AiP. The functions of these genes revealed two key cellular processes underlying AiP. One process is remodelling of the cytoskeleton, the cellular scaffolding, while the other is called autophagy which is a process critical for the maintenance of energy balance in a cell. The proposed work is to determine roles of these key cellular processes and other identified new regulators in mediating AiP. The outcome of this research will help us understand how dying cells talk to their neighbours to induce cell replacement. As AiP is relevant to both regeneration (tissue repair) and tumour growth (cancer) in mammals including humans, the proposed work can provide potential drug targets for regenerative medicine and cancer therapy.