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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

基本信息

批准号：
10673656
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
项目类别：
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/10673656
关键词：
Adopted Anti-Inflammatory Agents Apoptosis Apoptotic Autoimmunity Biological Cancer Intervention Caspase Cell Communication Cell Death Cell Survival Cells Compensation Defect Development Disease Doctor of Philosophy Drosophila genus Drosophila melanogaster Environment Generations Genes Genetic Genetic Models Genetic Screening Growth Hemocytes Homeostasis Human Induction of Apoptosis Investigation Macrophage Malignant Neoplasms Massachusetts Methods Mus Myocardial Infarction Natural regeneration Nerve Degeneration Organism Pathogenesis Pathologic Phenotype Principal Investigator Process Proliferating Radiation therapy Reactive Oxygen Species Regenerative response Regulation Relapse Research Resistance Signal Transduction Stroke Tissues Universities Xenopus behavior influence chemotherapy improved injury stressor medical schools model organism neoplastic cell novel therapeutic intervention programs regenerative tumor

项目摘要

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.

细胞凋亡和细胞凋亡诱导的机制和后果

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Tumor-promoting function of apoptotic caspases by an amplification loop involving ROS, macrophages and JNK in Drosophila.

通过涉及果蝇中的ROS，巨噬细胞和JNK的扩增环，凋亡caspase的肿瘤促进功能。

DOI：
10.7554/elife.26747
发表时间：
2017-08-30
期刊：
eLife
影响因子：
7.7
作者：
Pérez E;Lindblad JL;Bergmann A
通讯作者：
Bergmann A

Extracellular Reactive Oxygen Species Drive Apoptosis-Induced Proliferation via Drosophila Macrophages.

DOI：
10.1016/j.cub.2015.12.064
发表时间：
2016-03-07
期刊：
Current biology : CB
影响因子：
0
作者：
Fogarty CE;Diwanji N;Lindblad JL;Tare M;Amcheslavsky A;Makhijani K;Brückner K;Fan Y;Bergmann A
通讯作者：
Bergmann A

Transiently "Undead" Enterocytes Mediate Homeostatic Tissue Turnover in the Adult Drosophila Midgut.