Role of apoptosis for regenerative proliferation

描述(申请人提供)：凋亡诱导增殖(AIP)描述了最近发现的凋亡细胞有能力诱导邻近存活细胞的增殖，从而补偿他们的损失。例如，尽管电离辐射引发了高达60%的大量细胞凋亡组织损失，但果蝇的翅膀想象盘可以诱导再生细胞增殖，从而产生正常比例和大小的成年翅膀。出人意料的是，在包括果蝇、非洲爪哇、九头蛇、小鼠和人类癌症在内的几种生物中获得的证据表明，包括肿瘤在内的截肢或其他受损组织的再生AIP依赖于非凋亡功能中的凋亡caspase(高度特异的细胞死亡蛋白酶)。尽管在过去的几年里取得了进展，但仍然很差 了解半胱氨酸天冬氨酸氨基转移酶如何促进再生增殖中的这种非凋亡作用。这个项目的总体目标是利用果蝇作为基因发现的模型来识别AIP的基因并阐明AIP的机制。我们的方法是在上游诱导细胞凋亡，但同时在其促进AIP活性的下游阻断细胞凋亡。在这些条件下，细胞保持活着(不死)，但仍然可以促进AIP，因为凋亡的阻断是在其促进AIP活性的下游。因为“不死”细胞不会死亡，而是继续促进AIP，它们产生显著的过度生长表型，这为基因筛查提供了方便的分析方法。在这个项目中，将探索这些筛选分析，然后是已识别基因的表型特征，以解决这一目标。这个项目对于理解人类癌症也是非常相关的。肿瘤细胞和“不死”细胞有许多相似之处。肿瘤细胞通常由于凋亡基因的失活或抗凋亡基因的上调而丧失凋亡能力。如果这种凋亡阻断发生在潜在的不死肿瘤细胞AIP诱导活性的下游，这种活性可能会显著促进肿瘤的生长，这确实是最近所显示的。此外，放射和化疗试图通过杀死肿瘤细胞来治愈癌症。然而，经治疗的肿瘤经常复发，这可能是由于不死的肿瘤细胞促进AIP的活性所致。总之，这个项目有望提高我们对正常条件下的再生增殖和病理条件下的肿瘤表型的理解。

DESCRIPTION (provided by applicant): Apoptosis-induced proliferation (AiP) describes the recently made discovery that apoptotic cells have the ability to induce proliferation of neighboring surviving cells, thus compensating for their loss. For instance, despite massive apoptotic tissue loss of up to 60% triggered by ionizing radiation, Drosophila wing imaginal discs induce regenerative cell proliferation which generates adult wings of normal proportion and size. Unexpectedly, evidence obtained in several organisms including Drosophila, Xenopus, Hydra, Mouse and human cancer suggests that regenerative AiP of amputated or otherwise damaged tissues including tumors depends on apoptotic caspases (highly specific cell death proteases) in a non-apoptotic function. Although progress has been made in the last few years, it is still poorly understood how caspases promote this non- apoptotic role in regenerative proliferation. The overall objective of this project is to identify the genes and elucidate the mechanisms of AiP using Drosophila as a model of gene discovery. Our approach is to induce apoptosis upstream, but simultaneously block apoptosis downstream of its AiP-promoting activity. Under these conditions, cells are kept alive ('undead'), but can still promote AiP because the block of apoptosis is downstream of its AiP-promoting activity. Because 'undead' cells do not die, but continue to promote AiP, they produce significant overgrowth phenotypes which provide convenient assays for genetic screening. These screening assays followed by phenotypic characterization of the identified genes will be explored in this project to address the objective. This project is also very relevant for understanding of human cancer. There are many similarities between tumor cells and 'undead' cells. Tumor cells are often apoptosis-incompetent due to inactivation of apoptotic genes or upregulation of anti-apoptotic genes. If this block of apoptosis occurs downstream of a potentially AiP-inducing activity of 'undead' tumor cells, this activity may significantly contribute to tumor growth which has indeed recently been shown. Furthermore, radio- and chemotherapy attempt to cure cancer by killing tumor cells. However, relapse of treated tumors is frequently observed and may be due to AiP-promoting activity of 'undead' tumor cells. In summary, this project promises to improve our understanding of both regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.