Mechanisms and consequences of programmed cell death (apoptosis) and compensatory proliferation in Drosophila

细胞凋亡及其诱导的机制和后果 果蝇的增殖 主要研究者：Andreas Bergmann，Ph.D. 马萨诸塞州大学医学院，伍斯特，马萨诸塞州 细胞凋亡是细胞死亡的主要形式，对正常发育和组织至关重要。 多细胞生物体内平衡。细胞凋亡调控的缺陷导致了细胞凋亡的发生。 多种疾病的发病机制，包括与细胞死亡率降低相关的疾病 （癌症，自身免疫）或过度细胞死亡（神经变性，中风，心肌 梗塞）。凋亡细胞与其细胞环境相互作用并影响其行为 通过释放抗炎、促凋亡和抗凋亡以及促有丝分裂信号。释放 后者触发凋亡诱导的增殖（AiP），其描述了细胞凋亡的能力。 凋亡细胞诱导邻近存活细胞的再生增殖，从而 补偿他们的损失。出乎意料的是，在几种生物体中获得的证据， 果蝇、非洲爪蟾、水螅、小鼠和人类癌症表明， 截肢或其他损伤的组织包括肿瘤依赖于凋亡半胱天冬酶 （高度特异性的细胞死亡蛋白酶），除了但独立于它们的凋亡功能。 这项科学计划的总体目标是获得一个全面的 了解细胞凋亡和AiP调节的生物学原理， 多细胞生物，以确定和表征参与这些过程的基因， 来开发操控它们的方法我们用的是强大的基因模型生物 黑腹果蝇进行这些研究。我们已经建立了细胞凋亡的遗传模型 和AiP，并启动了正向遗传筛选，直接评估这些基因的遗传基础， 基本过程。本应用程序侧重于四个关键问题。1.微调情况如何 caspase的活性达到了多少？2.非凋亡细胞的半胱天冬酶的蛋白水解靶点是什么？ 函数的值？3.半胱天冬酶如何控制活性氧（ROS）的产生？ 4.巨噬细胞（血细胞）如何采用活化表型进行生长控制？ 这个项目对于了解人类癌症非常重要。我们的研究阐明了 潜在的肿瘤细胞增加其对凋亡的抗性的机制， 癌症，这可能会产生永生化（不死）细胞。此外，凋亡的肿瘤细胞 促进半胱天冬酶依赖性AiP。例如，尽管放射治疗和化学治疗试图 通过杀死肿瘤细胞来治愈癌症，经常观察到治疗的肿瘤复发， 这可能是由于垂死肿瘤细胞的AiP-promoting活性。因此，本研究的结果 该计划将大大提高我们对细胞凋亡和再生的理解， 正常条件下的增殖和病理条件下的肿瘤表型。

Mechanisms and Consequences of Apoptosis and Apoptosis-induced Proliferation in Drosophila Principal Investigator: Andreas Bergmann, Ph.D. University of Massachusetts Medical School, Worcester, MA Apoptosis is the major form of cell death that is critical for normal development and tissue homeostasis of multi-cellular organisms. Defects in the regulation of apoptosis contribute to the pathogenesis of multiple diseases including those associated with reduced rates of cell death (cancer, autoimmunity) or with excessive cell death (neurodegeneration, stroke, myocardial infarction). Apoptotic cells interact with and influence the behavior of their cellular environment by releasing anti-inflammatory, pro- and anti-apoptotic as well as mitogenic signals. The release of the latter triggers Apoptosis-induced Proliferation (AiP) which describes the ability of apoptotic cells to induce regenerative proliferation of neighboring surviving cells, thus compensating for their loss. 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 addition to, but independently of, their apoptotic function. The overall objective of this scientific program is to gain a comprehensive understanding of the biological principles that underlie the regulation of apoptosis and AiP in a multi-cellular organism, to identify and characterize the genes involved in these processes, and to develop methods to manipulate them. We are using the powerful genetic model organism Drosophila melanogaster for these studies. We have developed genetic models of apoptosis and AiP, and initiated forward genetic screens that directly assessed the genetic basis of these fundamental processes. This application focuses on four key questions. 1. How is the fine-tuning of caspase activity achieved? 2. What are the proteolytic targets of caspases for non-apoptotic functions? 3. How do caspases control the generation of reactive oxygen species (ROS) for AiP? 4. How do macrophages (hemocytes) adopt an activated phenotype for growth control? This program is very relevant for understanding of human cancer. Our studies elucidate mechanisms by which potential tumor cells increase their resistance to apoptosis, a hallmark of cancer, which may generate immortalized (undead) cells. Moreover, apoptotic tumor cells promote caspase-dependent AiP. For example, although radio- and chemotherapy attempt to cure cancer by killing tumor cells, relapse of treated tumors is frequently observed which may be due to an AiP-promoting activity of dying tumor cells. Therefore, the results of this research program will significantly improve our understanding of apoptosis and regenerative proliferation under normal conditions, and tumor phenotypes under pathological conditions.