Genetic Control of Programmed Cell Death (Apoptosis) and Compensatory Proliferation in Drosophila

果蝇程序性细胞死亡（细胞凋亡）和补偿性增殖的遗传控制

• 批准号: 9983071
• 负责人: ANDREAS BERGMANN
• 金额: $ 70.02万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983071
• 关键词: Adult; Amputation; Animal Model; Apoptosis; Apoptotic; Autoimmunity; Biological; Cancer Intervention; Caspase; Cell Death; Cell Proliferation; Cells; Defect; Development; Disease; Drosophila genus; Drosophila melanogaster; Genes; Genetic; Genetic Models; Genetic Screening; Homeostasis; Human; Injury; Investigation; Ionizing radiation; Lead; Malignant Neoplasms; Methods; Molecular Genetics; Mus; Myocardial Infarction; Natural regeneration; Nerve Degeneration; Organism; Pathogenesis; Pathologic; Phenotype; Physiological Processes; Principal Investigator; Process; Radio; Regenerative response; Regulation; Relapse; Resistance; Stress; Stroke; Tissues; Vertebrates; Wing; Xenopus; chemotherapy; developmental plasticity; gene discovery; genetic analysis; imaginal disc; improved; neoplastic cell; novel therapeutic intervention; programs; public health relevance; regenerative; tumor

 DESCRIPTION (provided by applicant): Programmed cell death (PCD) or apoptosis is a physiological process that is critical for normal development and tissue homeostasis. Defects in the regulation of PCD 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). 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. 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 the context of 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 genetic model organism Drosophila melanogaster for these studies. During Drosophila development many cells die by apoptosis. This cell death shares this developmental plasticity with vertebrates. Genetic screening for gene discovery and molecular genetic analysis in Drosophila promise considerable potential for advancing our understanding of the basic control mechanisms involved in the regulation of apoptosis and AiP in vertebrates including humans. This program is also 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, recent evidence has suggested that 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. In summary, this program promises to improve our understanding of apoptosis and regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.

 描述（由申请人提供）：程序性细胞死亡（PCD）或细胞凋亡是一种生理过程，对正常发育和组织稳态至关重要。PCD调节的缺陷导致多种疾病的发病机制，包括与细胞死亡率降低（癌症、自身免疫）或与过度细胞死亡（神经变性、中风、心肌梗死）相关的疾病。 凋亡诱导增殖（Apoptosis induced proliferation，AiP）是近年来发现的凋亡细胞具有诱导增殖的能力 相邻的存活细胞，从而补偿它们的损失。例如，尽管电离辐射引发了高达60%的大量凋亡组织损失，但果蝇翼盘仍会诱导再生细胞增殖，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）。 该科学计划的总体目标是全面了解多细胞生物体中细胞凋亡和AiP调节的生物学原理，识别和表征参与这些过程的基因，并开发操纵它们的方法。 我们正在使用遗传模式生物黑腹果蝇进行这些研究。在果蝇的发育过程中，许多细胞通过凋亡而死亡。这种细胞死亡与脊椎动物一样具有发育可塑性。果蝇基因发现和分子遗传学分析的遗传筛选承诺相当大的潜力，推进我们的理解的基本控制机制参与调节的脊椎动物，包括人类的细胞凋亡和AiP。 该计划也与了解人类癌症非常相关。我们的研究阐明了潜在的肿瘤细胞增加其对细胞凋亡的抵抗力的机制，细胞凋亡是癌症的标志，可能产生永生化（不死）细胞。此外，最近的证据表明，凋亡肿瘤细胞促进半胱天冬酶依赖性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，但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促进活性。 总之，该计划有望提高我们对正常条件下细胞凋亡和再生增殖以及病理条件下肿瘤表型的理解。