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.

凋亡通过雕刻组织，在多细胞生物中的发育和稳态中起着重要作用，删除不需要的结构，并消除异常，受伤或危险的细胞1。另外，定位凋亡途径是治疗顽固性疾病（例如癌症）的重要策略，而限制凋亡可能有益于治疗缺血性损伤和退化性疾病。虽然损失 - 或凋亡调节剂的功能获得的功能可以人为地允许细胞在正常检查点以外生存，通常认为凋亡是本质上不可逆的过程2,3。但是，我们最近发现了一个晚期凋亡在人和小鼠细胞中的自然可逆性4,5。垂死的细胞会逆转凋亡，并幸存，尽管经过了以前认为是无回报的检查站，包括 caspase-3激活和DNA损伤。只需清洗凋亡诱导剂就足够大多数垂死的细胞生存，大多数凋亡的标志都消失了，表明逆转凋亡是一种内源性细胞机制。值得注意的是，尽管大多数细胞完全恢复，但很小的部分逆转凋亡的细胞保留遗传改变并在较高的频率比对照细胞。我们认为凋亡的逆转可能是一种生理机制可以发挥多种有益的功能。在执行阶段逮捕凋亡原则上可能会促进细胞的存活，例如神经元和心肌细胞，难以替代。或者此外，我们将其命名为Anastasis（希腊语上升到生命）的恢复过程可以促进响应启动凋亡的环境或生理压力的遗传和表型多样性。这个原本有益的过程的负面副作用是致癌转化。我们已经发展了并测试了一个生物传感器，以检测果蝇果蝇在体内经历吻合的细胞。在具体目的1我们将检验以下假设：吻合曲与难以替代的拯救细胞的功能，因此限制了短暂损伤后的永久性组织损伤。我们还建议开发类似的用于哺乳动物细胞的生物传感器。在特定的目标2中，我们建议启动分子研究控制吻合的机制。拟议的工作有可能导致对和退化性疾病和癌症的治疗方法。