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（由申请人提供）：我们最近发现了一种新的生物现象，我们称之为 anastasis（希腊语“复活”）。 推翻了当前细胞死亡不可逆转的教条，我们发现多种正常和 癌细胞类型可以逆转这一过程、存活和增殖。这种可逆性甚至会发生 当细胞经历被广泛认为是不可逆转的事件后，包括半胱天冬酶的激活 酶和广泛的 DNA 损伤。值得注意的是，虽然大多数细胞完全恢复并修复受损的细胞 DNA，一些细胞保留突变，这增加了致癌转化的频率。这 阿纳斯塔西斯的发现至少具有五个范式转变的意义。首先，我们建议阿纳斯塔西斯 代表了以前未知的癌症原因，因此抑制 anastasis 应该可以预防癌症。 阿纳斯塔西斯还可以为长期观察到的反复损伤增加的现象提供解释。 癌症的发病率。其次，我们提出anastasis可以让肿瘤细胞逃避化疗 并产生耐药性。因此，抑制吻合可能会增强化疗的有效性。 放射治疗并预防复发。三、通过解剖挽救濒临死亡的细胞 可以限制由于短暂的环境压力或毒素暴露而造成的永久性组织损伤。 因此，增强吻合可能促进组织再生。第四，我们假设 anastasis 是 一种细胞生存机制，可以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减缓退行性疾病。第五，我们 提出通过 anastasis 获得突变的生殖细胞的存活提供了一种机制 当动物暴露在压力环境条件下时，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。这里我们建议测试一下 这些想法。我们设计了一种生物传感器，使我们能够识别和跟踪经历吻合的细胞 在体内，通过在 caspase 存活的细胞中永久表达 GFP 等报告基因 激活。我们建议在小鼠中使用这种生物传感器来测试短暂损伤和 压力会诱发肿瘤，肿瘤细胞会逃避治疗并导致癌症 产生耐药性。使用果蝇中的生物传感器，我们将测试 anastasis 的假设 增强人群的遗传多样性。此外，我们建议破译分子 允许细胞逆转死亡过程并存活的机制和识别分子方法 抑制或增强吻合。该项目的成功完成为公司的发展提供了潜力 针对癌症、神经退行性疾病和心力衰竭的革命性新疗法，并提供新的治疗方法 深入了解自然选择的进化机制。