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: 8720004
• 负责人: Denise J. Montell
• 金额: $ 18.8万
• 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/8720004
• 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

DESCRIPTION (provided by applicant): Apoptosis plays essential roles in development and homeostasis in multicellular organisms by sculpting tissues, deleting unwanted structures, and eliminating abnormal, injured or dangerous cells. 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 process. However, we recently discovered a natural reversibility of late-stage apoptosis in human and mouse cells. 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.

描述（由申请人提供）：细胞凋亡通过塑造组织、删除不需要的结构和消除异常、受损或危险的细胞，在多细胞生物体的发育和体内平衡中发挥重要作用。此外，靶向细胞凋亡途径是治疗难治性疾病如癌症的重要策略，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。虽然凋亡调节因子的功能丧失或获得可以人为地允许细胞存活超过正常检查点，但凋亡通常被认为是一个内在不可逆的过程。然而，我们最近发现人类和小鼠细胞晚期细胞凋亡的自然可逆性。死亡细胞可以逆转凋亡并存活，尽管已经通过了以前被认为是不可逆点的检查点，包括caspase-3激活和DNA损伤。简单地洗掉凋亡诱导物足以使大多数垂死细胞存活，并且凋亡的大多数标志消失，这表明凋亡的逆转是内源性细胞机制。值得注意的是，虽然大多数细胞完全恢复，但一小部分逆转凋亡的细胞保留遗传改变，并以比对照细胞更高的频率进行致癌转化。我们认为，逆转凋亡可能是一种生理机制，可以服务于几个有益的功能。在执行阶段阻止细胞凋亡原则上可以促进细胞的存活，例如神经元和心肌细胞，这些细胞是难以替代的。可替代地或另外地，该回收 这一过程，我们称之为anastasis（希腊语，意思是“上升到生命”），可以促进遗传和表型多样性，以应对引发细胞凋亡的环境或生理压力。这个有益过程的一个负面副作用是致癌转化。我们已经开发并测试了一种生物传感器，用于检测果蝇体内经历了anastasis的细胞。在具体目标1中，我们将检验以下假设：吻合功能是挽救难以替换的细胞，从而限制短暂损伤后的永久性组织损伤。我们还建议开发一种类似的生物传感器用于哺乳动物细胞。在具体目标2中，我们建议启动控制愈合的分子机制的研究。这项工作有可能导致对退行性疾病和癌症的新理解和治疗。