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）或细胞凋亡是一种对于正常发育和组织稳态至关重要的生理过程。 PCD 调节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）或细胞死亡过度（神经退行性疾病、中风、心肌梗塞）相关的疾病。 凋亡诱导增殖（AiP）描述了最近发现的凋亡细胞具有诱导增殖的能力 邻近的存活细胞，从而补偿它们的损失。例如，尽管电离辐射引发高达 60% 的大量凋亡组织损失，果蝇翅膀成虫盘仍诱导再生细胞增殖，从而产生正常比例和大小的成体翅膀。出乎意料的是，在包括果蝇、爪蟾、水螅、小鼠和人类癌症在内的多种生物体中获得的证据表明，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型生物果蝇进行这些研究。在果蝇发育过程中，许多细胞因凋亡而死亡。这种细胞死亡与脊椎动物共享这种发育可塑性。果蝇基因筛选和分子遗传学分析有望促进我们对包括人类在内的脊椎动物细胞凋亡和 AiP 调节所涉及的基本控制机制的理解。 该计划对于了解人类癌症也非常相关。我们的研究阐明了潜在肿瘤细胞增加对细胞凋亡的抵抗力的机制，细胞凋亡是癌症的一个标志，它可能会产生永生化（不死）细胞。此外，最近的证据表明，凋亡的肿瘤细胞促进 caspase 依赖性 AiP。例如，尽管放疗和化疗试图通过杀死肿瘤细胞来治愈癌症，但经常观察到治疗后的肿瘤复发，这可能是由于死亡肿瘤细胞的 AiP 促进活性。 总之，该计划有望提高我们对正常条件下的细胞凋亡和再生增殖以及病理条件下的肿瘤表型的理解。