Role of apoptosis for regenerative proliferation

描述（由申请人提供）：凋亡诱导的增殖（AiP）描述了最近发现的凋亡细胞具有诱导邻近存活细胞增殖的能力，从而补偿其损失。例如，尽管电离辐射引发了高达60%的大量凋亡组织损失，但果蝇翅膀成虫盘诱导再生细胞增殖，从而产生正常比例和大小的成虫翅膀。出乎意料的是，在包括果蝇、非洲爪蟾、水螅、小鼠和人类癌症的几种生物体中获得的证据表明，截肢或以其他方式受损的组织（包括肿瘤）的再生AiP依赖于非凋亡功能中的凋亡半胱天冬酶（高度特异性的细胞死亡蛋白酶）。虽然在过去几年中取得了进展，但仍然很差。 了解半胱天冬酶如何在再生增殖中促进这种非凋亡作用。 本项目的总体目标是利用果蝇作为基因发现的模型来鉴定AiP的基因并阐明其机制。我们的方法是在上游诱导凋亡，但同时阻断其AIP促进活性下游的凋亡。在这些条件下，细胞保持存活（“不死”），但仍然可以促进AiP，因为细胞凋亡的阻断是其AiP促进活性的下游。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，这为遗传筛选提供了方便的测定。在本项目中，将探索这些筛选试验，然后对已鉴定基因进行表型表征，以实现这一目标。该项目也与了解人类癌症非常相关。肿瘤细胞和“不死”细胞之间有许多相似之处。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不能凋亡。如果这种细胞凋亡的阻断发生在“不死”肿瘤细胞的潜在AiP诱导活性的下游，则这种活性可能显著促进肿瘤生长，这在最近确实被证明。此外，放疗和化疗试图通过杀死肿瘤细胞来治愈癌症。然而，经常观察到接受治疗的肿瘤复发，这可能是由于“不死”肿瘤细胞的Aip促进活性造成的。 总之，该项目有望提高我们对正常条件下再生增殖和病理条件下肿瘤表型的理解。

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.