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: 9099812
• 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/9099812
• 关键词: Adult; Animals; Automobile Driving; Biological Phenomena; Brain; Cancer Etiology; Cardiac Myocytes; Caspase; Cell Death; Cell Survival; Cells; Cessation of life; DNA Damage; Degenerative Disorder; Drug resistance; Effectiveness; Environment; Enzymes; Event; Evolution; Frequencies; Genetic Variation; Germ Cells; Greek; Human body; Incidence; Injury; Life; Malignant Neoplasms; Molecular; Mutation; Neurons; Normal Cell; Oncogenic; Physiological; Process; Proliferating; Radiation therapy; Relapse; Staging; Stress; Testing; Tissues; Toxin; cancer cell; cell type; chemotherapy; design; experience; neoplastic cell; novel therapeutic intervention; prevent; repaired; 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 chemo- and 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 biosen

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”）。推翻了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这一过程，存活和增殖。这种可逆性甚至发生在细胞经历了被广泛认为是不可逆点的事件之后，包括半胱天冬酶的激活和广泛的DNA损伤。值得注意的是，虽然大多数细胞完全恢复和修复其受损的DNA，但一些细胞保留突变，这增加了致癌转化的频率。anastasis的发现至少有五个范式转变的影响。第一、 我们认为，anastasis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还可以解释长期观察到的重复性损伤增加癌症发病率的现象。第二，我们提出，anastasis允许肿瘤细胞逃避化疗和发展耐药性。因此，抑制血管吻合可以提高化疗和放疗的有效性，并防止复发。第三，通过缝合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，增强吻合可以促进组织再生。第四，我们认为anastasis是一种细胞生存机制，可以保护难以替代的细胞，如成年大脑或心肌细胞中的神经元，因此促进anastasis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生存提供了一种机制，以提高遗传多样性，正是当动物暴露于压力的环境条件。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