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（希腊语为“复活”）。 推翻目前细胞死亡是不可逆的教条，我们发现，各种正常和 癌细胞类型可以逆转该过程，存活并增殖。这种可逆性甚至发生在 在细胞经历被广泛认为是不可逆点的事件后，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和修复受损的细胞， DNA，一些细胞保留突变，这增加了致癌转化的频率。的 anastasis的发现至少有五个范式转变的影响。首先，我们认为， 代表了一种以前未知的癌症原因，因此抑制anastasis应该可以预防癌症。 Anastasis还可以为长期观察到的重复性损伤增加提供解释。 癌症的发病率。第二，我们提出，anastasis允许肿瘤细胞逃避化疗 并进化出抗药性。因此，抑制吻合可以增强化疗的有效性， 放射治疗和预防复发。第三，通过anastasis挽救濒临死亡的细胞 可以限制由于短暂的环境应力或毒素暴露造成的永久性组织损伤。 因此，增强吻合可以促进组织再生。第四，我们认为anastasis是 一种细胞存活机制，保护难以取代的细胞，如成人大脑中的神经元 或心肌细胞，因此促进愈合可以预防或减缓退行性疾病。五是 我认为，通过回授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，可以精确地增强遗传多样性。 这可以加速进化过程中对不断变化的环境的适应。在这里，我们建议测试 这些想法。我们设计了一种生物传感器，可以让我们识别和跟踪经历愈合的细胞， 在体内通过在半胱天冬酶存活的细胞中产生诸如GFP的报告基因的永久表达 activation.使用这种生物传感器在小鼠中，我们建议测试的假设，短暂的损伤和 应激诱导anastasis，anastasis导致癌症并允许肿瘤细胞逃避治疗， 产生抗药性。利用果蝇中的生物传感器，我们将测试这一假设， 增强了种群的遗传多样性。此外，我们还打算破译 机制，使细胞逆转死亡过程和生存，并确定分子方法 以抑制或增强愈合。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 洞察自然选择的进化机制。