Reversal of apoptosis:an in vivo mechanism for cytoprotection and mutagenesis

细胞凋亡的逆转：细胞保护和诱变的体内机制

基本信息

批准号：
8589289
负责人：
Denise J. Montell
金额：
$ 22.96万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8589289
关键词：
Adverse effects Animals Apoptosis Apoptotic Biochemical Markers Biosensor Bulla Cardiac Myocytes Caspase Cell Death Process Cell Fraction Cell Line Cell Survival Cells Cellular Stress Cessation of life Cytoprotection DNA Damage Degenerative Disorder Development Disease Drosophila genus Drosophila melanogaster Drug resistance Event Evolution Female Ferrets Frequencies Funding Genetic Germ Cells Goals Greek Hela Cells Hepatocyte Homeostasis Human Injury Kupffer Cells Label Lead Life Malignant Neoplasms Mammalian Cell Membrane Mitochondria Molecular Mus Mutagenesis Mutation Names Neurons Nuclear Oncogenic Organism Outer Mitochondrial Membrane Ovary Parkinson Disease Pathway interactions Physical condensation Physiological Play Prevention strategy Process Rattus Recovery Research Role Staging Starvation Stem cells Stimulus Stress Structure Testing Time Tissues Work annexin A5 caspase-3 cell type cytochrome c feeding fly follow-up gain of function heart cell in vivo injured public health relevance response tool treatment strategy

项目摘要

Apoptosis plays essential roles in development and homeostasis in multicellular organisms by sculpting tissues, deleting unwanted structures, and eliminating abnormal, injured or dangerous cells1. In addition, targeting apoptotic pathways is an important strategy for treatment of intractable diseases such as cancer, whereas limiting apoptosis may be beneficial for treating ischemic injury and degenerative disorders. Although loss- or gain-of-function of apoptotic regulators can artificially allow cells to survive beyond normal checkpoints, apoptosis is generally assumed to be an intrinsically irreversible process2,3. However, we recently discovered a natural reversibility of late-stage apoptosis in human and mouse cells4,5. Dying cells can reverse apoptosis and survive, despite having passed through checkpoints previously believed to be the point of no return, including caspase-3 activation and DNA damage. Simply washing away apoptotic inducers is sufficient to allow the majority of dying cells to survive and most hallmarks of apoptosis to vanish, indicating that reversal of apoptosis is an endogenous cellular mechanism. Notably, while most cells recover completely, a small fraction of cells that reverse apoptosis retain genetic alterations and undergo oncogenic transformation at a higher frequency than control cells. We propose that reversal of apoptosis may be a physiological mechanism that can serve several beneficial functions. Arrest of apoptosis at the execution stage could in principle promote survival of cells, such as neurons and heart muscle cells, which are difficult to replace. Alternatively or in addition, this recovery process, which we have named anastasis (Greek for rising to life), could promote genetic and phenotypic diversity in response to environmental or physiological stresses that initiate apoptosis. A negative side effect of this otherwise beneficial process is oncogenic transformation. We have developed and tested a biosensor to detect cells that have undergone anastasis in vivo in Drosophila melanogaster. In specific aim 1 we will test the hypothesis that anastasis functions to salvage cells that are difficult to replace, thus limiting permanent tissue damage following transient insults. We also propose to develop a similar biosensor for use in mammalian cells. In specific aim 2 we propose to initiate studies of the molecular mechanisms controlling anastasis. The proposed work has the potential to lead to a new understanding of and treatments for degenerative diseases and cancer.

细胞凋亡通过塑造组织，在多细胞生物的发育和稳态中发挥重要作用，删除不需要的结构，并消除异常、受伤或危险的细胞1。此外，针对细胞凋亡途径是治疗癌症等疑难疾病的重要策略，而限制细胞凋亡可能有益于治疗缺血性损伤和退行性疾病。尽管损失或凋亡调节因子的功能获得可以人为地允许细胞在正常检查点之外存活，细胞凋亡通常被认为是本质上不可逆的过程2,3。然而，我们最近发现了一个人类和小鼠细胞晚期细胞凋亡的自然可逆性4,5。死亡细胞可以逆转细胞凋亡尽管已经通过了以前被认为是没有回头路的检查站，但仍然生存下来，包括 caspase-3 激活和 DNA 损伤。简单地洗掉凋亡诱导剂就足以使大多数垂死细胞得以存活，大多数细胞凋亡标志消失，表明细胞凋亡的逆转细胞凋亡是一种内源性细胞机制。值得注意的是，虽然大多数细胞完全恢复，但一小部分细胞逆转细胞凋亡的细胞保留遗传改变并以更高的速度进行致癌转化频率高于对照细胞。我们认为细胞凋亡的逆转可能是一种生理机制可以起到多种有益的作用。在执行阶段阻止细胞凋亡原则上可以促进神经元和心肌细胞等难以替代的细胞的存活。或者或者在此外，我们将这一恢复过程命名为 anastasis（希腊语，意为复活），可以促进响应引发细胞凋亡的环境或生理应激的遗传和表型多样性。这一有益过程的负面影响是致癌转化。我们开发了并测试了一种生物传感器来检测果蝇体内已经发生转移的细胞。在具体目标 1 我们将检验这样的假设：吻合功能可以挽救难以替代的细胞，从而限制短暂损伤后的永久性组织损伤。我们还建议开发一个类似的用于哺乳动物细胞的生物传感器。在具体目标 2 中，我们建议启动分子研究控制 anastasis 的机制。拟议的工作有可能导致人们对和退行性疾病和癌症的治疗。