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

果蝇程序性细胞死亡（细胞凋亡）和代偿性增殖的机制和后果

• 批准号: 10206978
• 负责人: ANDREAS BERGMANN
• 金额: $ 72.12万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206978
• 关键词: Adopted; Amputation; Animal Model; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Autoimmunity; Biological; Cancer Intervention; Caspase; Cell Death; Cells; Defect; Development; Disease; Doctor of Philosophy; Drosophila genus; Drosophila melanogaster; Environment; Generations; Genes; Genetic; Genetic Models; Genetic Screening; Growth; Hemocytes; Homeostasis; Human; Injury; Investigation; Lead; Malignant Neoplasms; Massachusetts; Methods; Mus; Myocardial Infarction; Natural regeneration; Nerve Degeneration; Organism; Pathogenesis; Pathologic; Phenotype; Principal Investigator; Process; Radio; Reactive Oxygen Species; Regenerative response; Regulation; Relapse; Research; Resistance; Signal Transduction; Stress; Stroke; Tissues; Universities; Xenopus; behavior influence; chemotherapy; improved; macrophage; medical schools; neoplastic cell; novel therapeutic intervention; programs; regenerative; tumor

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.

凋亡和凋亡诱导的机制和后果 果蝇的增殖 首席研究员：Andreas Bergmann博士 马萨诸塞大学医学院，马萨诸塞州伍斯特 凋亡是细胞死亡的主要形式，对正常发育和组织至关重要 多细胞生物的稳态。凋亡调节的缺陷有助于 多种疾病的发病机理，包括与细胞死亡率降低有关的疾病 （癌症，自身免疫性）或过度细胞死亡（神经变性，中风，心肌 梗塞）。凋亡细胞与细胞环境的行为相互作用并影响 通过释放抗炎，促和抗凋亡以及有丝分裂信号。版本 后者触发了凋亡引起的增殖（AIP），该增殖（AIP）描述了 凋亡细胞诱导邻近存活细胞的再生增殖，因此 补偿他们的损失。出乎意料的是，在包括 果蝇，爪蟾，九头蛇，小鼠和人类癌症表明 包括肿瘤在内的截肢或以其他方式受损的组织取决于凋亡的胱天蛋白酶 （高度特异性的细胞死亡蛋白酶）除了但独立于其凋亡功能。 该科学计划的总体目标是获得一个全面的 了解基于调节凋亡和AIP的生物学原理 多细胞生物，以识别和表征这些过程中涉及的基因，并 开发操纵它们的方法。我们正在使用强大的遗传模型生物 这些研究的果蝇果蝇。我们已经开发了凋亡的遗传模型 和AIP，并启动了直接评估这些遗传基础的正向遗传筛选 基本过程。该应用程序着重于四个关键问题。 1。微调如何 胱天蛋白酶活性的实现？ 2。非凋亡的胱天蛋白酶的蛋白水解靶标是什么 功能？ 3。胱天蛋白酶如何控制AIP的活性氧（ROS）的产生？ 4。巨噬细胞（血细胞）如何采用活化的表型来进行生长控制？ 该计划与对人类癌症的理解非常相关。我们的研究阐明了 潜在肿瘤细胞增加对凋亡的抗性的机制，这是 癌症，可能会产生永生的（不死）细胞。此外，凋亡肿瘤细胞 促进caspase依赖性AIP。例如，尽管放射和化学疗法试图 通过杀死肿瘤细胞来治愈癌症，经常观察到治疗肿瘤的复发，这可能 是由于垂死的肿瘤细胞的AIP促进活性。因此，这项研究的结果 程序将大大提高我们对凋亡和再生的理解 在正常条件下的增殖和病理条件下的肿瘤表型。