Anastasis, a new mechanism driving cell survival and evolution

Anastasis，驱动细胞生存和进化的新机制

• 批准号: 8750779
• 负责人: Denise J. Montell
• 金额: $ 76.75万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-24 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8750779
• 关键词: Adult; Animals; Automobile Driving; Biological Phenomena; Biosensor; Brain; Cancer Etiology; Cardiac Myocytes; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; DNA Damage; Degenerative Disorder; Drosophila genus; Drug resistance; Effectiveness; Environment; Enzymes; Event; Evolution; Frequencies; Genetic Variation; Germ Cells; Greek; Heart failure; Human body; Incidence; Injury; Life; Malignant Neoplasms; Molecular; Mus; Mutation; Natural Selections; Neurodegenerative Disorders; Neurons; Normal Cell; Oncogenic; Physiological; Population; Process; Proliferating; Radiation therapy; Relapse; Reporter; Staging; Stress; Testing; Tissues; Toxin; cancer cell; cancer therapy; cell type; chemotherapy; design; experience; in vivo; insight; neoplastic cell; novel therapeutic intervention; prevent; repaired; therapy development; tissue regeneration

DESCRIPTION (provided by applicant): We recently discovered a new biological phenomenon, which we call anastasis (Greek for “rising to life”). Overturning the current dogma that cell death is irreversible, we found that a variety of normal and cancer cell types can reverse the process, survive, and proliferate. This reversibility takes place even after cells experience events widely believed to be points of no return, including activation of caspase enzymes and widespread DNA damage. Notably, while most cells fully recover and repair their damaged DNA, some cells retain mutations, and this increases the frequency of oncogenic transformation. The discovery of anastasis has at least five paradigm-shifting implications. First, we suggest that anastasis represents a previously unknown cause of cancer, so inhibiting anastasis should prevent cancer. Anastasis could also offer an explanation for the longstanding observation that repeated injury increases the incidence of cancer. Second, we propose that anastasis allows tumor cells to escape chemotherapy and evolve drug resistance. Therefore, inhibiting anastasis may enhance the effectiveness of chemoand radiation therapies and prevent relapses. Third, salvaging cells on the brink of death via anastasis may limit permanent tissue injury due to transient environmental stresses or toxin exposures. Consequently, enhancing anastasis may promote tissue regeneration. Fourth, we posit that anastasis is a cell survival mechanism that protects cells that are difficult to replace such as neurons in the adult brain or heart muscle cells, so promoting anastasis could prevent or slow degenerative diseases. Fifth, we propose that the survival of germ cells with mutations acquired through anastasis provides a mechanism to enhance genetic diversity precisely when animals are exposed to stressful environmental conditions. This could accelerate adaptation to changing environments during evolution. Here we propose to test these ideas. We designed a biosensor that will allow us to identify and track cells that undergo anastasis in vivo by creating permanent expression of a reporter such as GFP in cells that survive caspase activation. Using this biosensor in mice we propose to test the hypotheses that transient injuries and stresses induce anastasis, that anastasis causes cancer and allows tumor cells to evade therapies and develop drug resistance. Using the biosensor in Drosophila, we will test the hypothesis that anastasis enhances genetic diversity in the population. In addition, we propose to decipher the molecular mechanisms that allow cells to reverse the dying process and survive and identify molecular approaches to inhibit or enhance anastasis. The successful completion of this project offers the potential to develop revolutionary new therapies for cancer, neurodegenerative diseases, and heart failure, and provide new insight into the mechanisms of evolution by natural selection.

描述（由适用提供）：我们最近发现了一种新的生物学现象，我们称之为Anastasis（希腊语“兴起来栩栩如生”）。 推翻了当前的教条，即细胞死亡是不可逆的，我们发现多种正常和 癌细胞类型可以扭转这一过程，生存和增殖。这种可逆性甚至发生了 在细胞经历广泛认为是无回报点的事件之后，包括激活caspase 酶和广泛的DNA损伤。值得注意的是，大多数细胞完全恢复并修复了它们的损坏 DNA，一些细胞保留突变，这增加了致癌转化的频率。这 发现anastasis至少具有五个范式转移含义。首先，我们建议anastasis 代表了以前未知的癌症原因，因此抑制吻合应预防癌症。 anastasis也可以为长期观察结果提供解释，即反复伤害增加 癌症的事件。其次，我们建议anastasis允许肿瘤细胞逃脱化疗 和进化耐药性。因此，抑制吻合可能会提高化学和化学的有效性 辐射疗法并防止继电器。第三，通过anastasis的死亡砖上的挽救细胞 由于瞬时环境应力或毒素暴露，可能会限制永久性组织损伤。 因此，增强吻合可能会促进组织再生。第四，我们肯定anastasis是 一种细胞存活机制，可保护难以替代的细胞，例如成人大脑中的神经元 或心肌细胞，因此促进吻合可以预防或缓慢的退化性疾病。第五，我们 提出的，即通过吻合获得突变的生殖细胞的存活提供了一种机制 当动物暴露于压力大的环境条件时，请精确地增强遗传多样性。 这可以加速对进化过程中不断变化的环境的适应。在这里我们建议测试 这些想法。我们设计了一个生物传感器，该生物传感器将使我们能够识别和跟踪经历吻合的细胞 在体内通过在caspase中生存的细胞中的记者的永久表达（例如GFP）的永久表达 激活。在小鼠中使用该生物传感器，我们建议测试瞬时损伤和 压力会诱导吻合，吻合会导致癌症，并使肿瘤细胞逃避疗法，并且 发展耐药性。在果蝇中使用生物传感器，我们将检验以下假设：anastasis 增强人群中的遗传多样性。另外，我们提出破译分子 允许细胞扭转垂死过程并存活并识别分子方法的机制 抑制或增强吻合。该项目的成功完成提供了发展的潜力 革命性的癌症，神经退行性疾病和心力衰竭的新疗法，并提供新的 洞悉自然选择进化的机制。