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; 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）：凋亡通过雕刻组织，删除不需要的结构并消除异常，受伤或危险细胞，在多细胞生物中发育和稳态中起着重要作用。此外，靶向凋亡途径是治疗棘手疾病（例如癌症）的重要策略，而限制凋亡可能对治疗缺血性损伤和退化性疾病有益。尽管凋亡调节剂的丧失或功能损失可以人为地允许细胞在正常检查点上生存，但通常认为凋亡是一种本质上不可逆的过程。但是，我们最近发现了人和小鼠细胞中晚期凋亡的自然可逆性。垂死的细胞可以逆转凋亡并生存，尽管已经通过了以前认为是无回报的检查点，包括caspase-3激活和DNA损伤。只需清洗凋亡诱导剂就足以使大多数垂死的细胞生存，大多数凋亡的标志都消失了，这表明凋亡的逆转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，但逆转凋亡的一小部分细胞保留了遗传改变并在较高的频率下进行致癌细胞转化。我们认为凋亡的逆转可能是可以发挥多种有益功能的生理机制。在执行阶段的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，这些细胞难以替代。或者，此恢复 我们将其命名为Anastasis的过程（希腊语上升为生命），可以促进造成细胞凋亡的环境或生理压力的响应，以促进遗传和表型多样性。这个原本有益的过程的负面副作用是致癌转化。我们已经开发并测试了一个生物传感器，以检测在果蝇中经体体内吻合的细胞。在特定的目标1中，我们将测试以下假设：吻合曲与难以替代的挽救细胞的功能，从而限制了短暂损伤后的永久组织损伤。我们还建议开发类似的生物传感器，用于哺乳动物细胞。在特定目标2中，我们建议启动对控制吻合的分子机制的研究。拟议的工作有可能导致对退行性疾病和癌症的新理解和治疗。