Role of apoptosis for regenerative proliferation

细胞凋亡在再生增殖中的作用

基本信息

批准号：
8723260
负责人：
ANDREAS BERGMANN
金额：
$ 44.27万
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：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8723260
关键词：
Address Adult Animal Model Apoptosis Apoptotic Biological Assay Caspase Cell Proliferation Cells Drosophila genus Drosophila melanogaster Ensure Equilibrium Family member Gene Order Genes Genetic Models Genetic Screening Goals Growth Homeostasis Homologous Gene Human Hydra Polyps Injury Ionizing radiation JNK-activating protein kinase Lead Malignant Neoplasms Mediating Modeling Mus Natural regeneration Organism Phenotype Physiological Planarians Process Radiation therapy Relapse Research Role Signal Transduction Stress Tissues Up-Regulation Wing Work Xenopus cell injury cell suicide chemotherapy cytokine gene discovery genome wide association study imaginal disc improved irradiation killings neoplastic cell novel therapeutic intervention public health relevance regenerative response screening tissue regeneration tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): 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. Although progress has been made in the last few years, it is still poorly understood how caspases promote this non- apoptotic role in regenerative proliferation. The overall objective of this project is to identify the genes and elucidate the mechanisms of AiP using Drosophila as a model of gene discovery. Our approach is to induce apoptosis upstream, but simultaneously block apoptosis downstream of its AiP-promoting activity. Under these conditions, cells are kept alive ('undead'), but can still promote AiP because the block of apoptosis is downstream of its AiP-promoting activity. Because 'undead' cells do not die, but continue to promote AiP, they produce significant overgrowth phenotypes which provide convenient assays for genetic screening. These screening assays followed by phenotypic characterization of the identified genes will be explored in this project to address the objective. This project is also very relevant for understanding of human cancer. There are many similarities between tumor cells and 'undead' cells. Tumor cells are often apoptosis-incompetent due to inactivation of apoptotic genes or upregulation of anti-apoptotic genes. If this block of apoptosis occurs downstream of a potentially AiP-inducing activity of 'undead' tumor cells, this activity may significantly contribute to tumor growth which has indeed recently been shown. Furthermore, radio- and chemotherapy attempt to cure cancer by killing tumor cells. However, relapse of treated tumors is frequently observed and may be due to AiP-promoting activity of 'undead' tumor cells. In summary, this project promises to improve our understanding of both regenerative proliferation under normal conditions and tumor phenotypes under pathological conditions.

描述（由申请人提供）：凋亡诱导的增殖（AIP）描述了最近发现的发现，凋亡细胞具有诱导邻近存活细胞的增殖的能力，从而补偿了它们的损失。例如，尽管有电离辐射触发的大量凋亡组织损失多达60％，但果蝇翼假想盘仍会诱导再生细胞增殖，从而产生正常比例和大小的成年翅膀。出乎意料的是，在包括果蝇，爪蟾，hydra，小鼠和人类癌症在内的几种生物中获得的证据表明，在非凋亡功能中，包括肿瘤的截肢或其他受损组织的再生AIP取决于凋亡的caspase（高度特异性细胞死亡蛋白酶）。尽管过去几年取得了进展，但仍然很差了解胱天蛋白酶在再生增殖中如何促进这种非凋亡作用。该项目的总体目的是使用果蝇作为基因发现模型来识别基因并阐明AIP的机制。我们的方法是诱导上游凋亡，但同时阻止其AIP促进活性的凋亡。在这些条件下，细胞保持活力（“亡灵”），但仍然可以促进AIP，因为凋亡的块是其促进AIP活性的下游。因为“亡灵”细胞不会死亡，而是继续促进AIP，因此它们会产生明显的过度生长表型，从而为遗传筛查提供方便的测定法。这些筛选测定后，然后在该项目中探索确定基因的表型表征，以解决目标。该项目也与对人类癌症的理解非常相关。肿瘤细胞和“不死”细胞之间有许多相似之处。由于凋亡基因失活或抗凋亡基因的上调，肿瘤细胞通常是凋亡不足的。如果这种细胞凋亡发生在“不死”肿瘤细胞的潜在诱导活性的下游，则该活性可能会显着促进肿瘤生长，这确实已显示出来。此外，放射性和化学疗法试图通过杀死肿瘤细胞来治愈癌症。但是，经常观察到治疗肿瘤的复发，可能是由于“亡灵”肿瘤细胞的AIP促进活性。总而言之，该项目有望在正常条件下和病理条件下对肿瘤表型下的再生增殖的理解提高我们的理解。