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

• 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
• 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

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.

通过塑造组织，细胞凋亡在多细胞生物体的发育和动态平衡中起着至关重要的作用， 删除不需要的结构，消除异常、受伤或危险的细胞1。此外，目标明确 细胞凋亡通路是治疗癌症等顽固性疾病的重要策略，而 限制细胞凋亡可能有利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增强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一个本质上不可逆的过程2，3。然而，我们最近发现了一个 人和小鼠细胞晚期凋亡的自然可逆性4，5.死亡的细胞可以逆转细胞的凋亡和 幸存下来，尽管已经通过了以前被认为是不归点的检查站，包括 Caspase-3激活和DNA损伤。简单地洗掉凋亡诱导剂就足以让 大多数垂死的细胞存活下来，大多数凋亡的标志消失，这表明 细胞凋亡是一种内源性的细胞机制。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了基因改变并经历了更高水平的致癌转化 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 可以起到几种有益的作用。在执行阶段阻止细胞凋亡原则上可以促进 细胞的存活，如神经元和心肌细胞，这些细胞很难被取代。可供选择或在 此外，这一恢复过程，我们将其命名为Anastsis(希腊语，意为复活)，可能会促进 对启动细胞凋亡的环境或生理压力作出反应的遗传和表型多样性。 这个原本有益的过程的一个负面副作用是致癌转化。我们已经开发出 并测试了一种生物传感器，以检测在体内经历了黑腹果蝇转移的细胞。在……里面 具体目标1我们将检验Anastasis的功能是挽救难以替代的细胞的假设， 从而限制了短暂侮辱后的永久性组织损伤。我们还建议开发一种类似的 用于哺乳动物细胞的生物传感器。在具体目标2中，我们建议启动对分子的研究 控制阿纳斯塔西病的机制。拟议的工作有可能导致对和 退化性疾病和癌症的治疗。