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:10447748
- 负责人:
- 金额:$ 72.12万
- 依托单位:
- 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:
- 关键词:AdoptedAmputationAnimal ModelAnti-Inflammatory AgentsApoptosisApoptoticAutoimmunityBiologicalCancer InterventionCaspaseCell DeathCellsDefectDevelopmentDiseaseDoctor of PhilosophyDrosophila genusDrosophila melanogasterEnvironmentGenerationsGenesGeneticGenetic ModelsGenetic ScreeningGrowthHemocytesHomeostasisHumanInjuryInvestigationLeadMalignant NeoplasmsMassachusettsMethodsMusMyocardial InfarctionNatural regenerationNerve DegenerationOrganismPathogenesisPathologicPhenotypePrincipal InvestigatorProcessRadioReactive Oxygen SpeciesRegenerative responseRegulationRelapseResearchResistanceSignal TransductionStressStrokeTissuesUniversitiesXenopusbehavior influencechemotherapyimprovedmacrophagemedical schoolsneoplastic cellnovel therapeutic interventionprogramsregenerativetumor
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,
截肢或以其他方式受损的组织(包括肿瘤)取决于细胞凋亡半胱天冬酶
(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?
功能?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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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ANDREAS BERGMANN其他文献
ANDREAS BERGMANN的其他文献
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{{ truncateString('ANDREAS BERGMANN', 18)}}的其他基金
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 - 财政年份:2016
- 资助金额:
$ 72.12万 - 项目类别:
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 - 财政年份:2016
- 资助金额:
$ 72.12万 - 项目类别:
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:
10673656 - 财政年份:2016
- 资助金额:
$ 72.12万 - 项目类别:
Role of apoptosis for regenerative proliferation
细胞凋亡在再生增殖中的作用
- 批准号:
8723260 - 财政年份:2013
- 资助金额:
$ 72.12万 - 项目类别:
Role of apoptosis for regenerative proliferation
细胞凋亡在再生增殖中的作用
- 批准号:
8879171 - 财政年份:2013
- 资助金额:
$ 72.12万 - 项目类别:
Role of apoptosis for regenerative proliferation
细胞凋亡在再生增殖中的作用
- 批准号:
8573515 - 财政年份:2013
- 资助金额:
$ 72.12万 - 项目类别:
Induction of Programmed Cell Death by cellular Mis-specification
细胞错误指定诱导程序性细胞死亡
- 批准号:
7372286 - 财政年份:2007
- 资助金额:
$ 72.12万 - 项目类别:
Induction of Programmed Cell Death by cellular Mis-specification
细胞错误指定诱导程序性细胞死亡
- 批准号:
7672270 - 财政年份:2007
- 资助金额:
$ 72.12万 - 项目类别:
Genetic Control of Non-Autonomous Survival in Drosophila
果蝇非自主生存的遗传控制
- 批准号:
8367119 - 财政年份:2007
- 资助金额:
$ 72.12万 - 项目类别:
Genetic Control of Non-Autonomous Survival in Drosophila
果蝇非自主生存的遗传控制
- 批准号:
7636765 - 财政年份:2007
- 资助金额:
$ 72.12万 - 项目类别:
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