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中文摘要
翻译
吻合:一种新的细胞存活机制
英文摘要
Anastasis: A Novel Cell Survival Mechanism Project Summary Anastasis is a newly discovered cell recovery mechanism that rescues apoptotic cells from the brink of death. Challenging the classic view of irreversible apoptosis, we have discovered robust reversibility of apoptosis in three types of mouse/rat primary cells, twelve human cancer cell lines, and egg chambers in fruit flies. What are the physiological functions, pathological roles, and therapeutic potentials of anastasis? Anastasis could be an unexpected cytoprotective mechanism for preserving terminally differentiated cells and tissues that are difficult to replace, such as cardiomyocytes and neurons. If true, enhancing anastasis may be beneficial for treating heart failure and brain injury. Besides, anastasis could be an unrecognized escape tactic enabling cancer cells to survive cancer therapy, thereby contributing to disease recurrence. If confirmed, suppressing anastasis in dying cancer cells may promote cancer cell death and reduce the chances of recurrence. Anastasis may also play important roles in limiting apoptosis during embryonic development and normal homeostasis. If identified, understanding its regulation can provide new insights into the control of cell death and survival in physiological conditions. However, there are several challenges of testing these hypotheses. It is difficult to track anastasis, especially in vivo, because cells that have reversed apoptosis are morphologically indistinguishable from healthy cells. There are no anastasis-specific hallmarks identified, and the regulators of anastasis remain undiscovered. Here, we will overcome many of these challenges by developing a novel and highly specific tracking system to label anastatic cells for mammalian studies, and to identify the key regulators of anastasis. To mark anastatic cells, we will create an anastasis biosensor that can tag anastatic cells with permanent expression of a fluorescent protein only after they have recovered from both mitochondrial outer membrane permeabilization (MOMP) and caspase-3 activation, the two most recognized apoptotic events, making this biosensor system highly specific to anastasis. We will establish anastasis biosensor stable cell lines to determine reversibility of apoptosis in vitro, and will employ biosensor xenografts to interrogate anastasis in vivo using clinically relevant mouse models. To elucidate the mechanism of anastasis, we will identify its key regulators, through proteomics, genetics, and pharmacological approaches. We will identify which genes exhibit up- or down-expression (potential anastasis regulators, and therapeutic targets) during different stages of anastasis, determine whether specific post-translational modifications distinguish anastatic cells, establish whether cells that recover from different cell death inductions share similar molecular features, and investigate how interfering with anastasis regulator candidates could modulate the reversibility of apoptosis. We will identify small molecules that target the candidates by bioinformatics, and test their efficacy in promoting or suppressing anastasis in vitro. Successful completion of this project will generate essential tools and knowledge for studying anastasis, thereby laying a strong foundation for developing revolutionary new therapeutic approaches by controlling anastasis.
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Elucidating connections between anastasis and cancer drug resistance
  • 批准号:
    10056879
  • 项目类别:
  • 资助金额:
    $41.11万
  • 财政年份:
    2020
  • 负责人:
    Ho Lam Tang
  • 依托单位:
Cell survival by anastasis, a novel therapeutic target in cancer
  • 批准号:
    9751798
  • 项目类别:
  • 资助金额:
    $16.2万
  • 财政年份:
    2017
  • 负责人:
    Ho Lam Tang
  • 依托单位:
国内基金
海外基金
Epac1/2通过蛋白酶体调控中性粒细胞NETosis和Apoptosis在急性肺损伤中的作用研究
  • 批准号:
    LBY21H010001
  • 项目类别:
    省市级项目
  • 资助金额:
    --
  • 批准年份:
    2020
  • 负责人:
    郑绪阳
  • 依托单位:
基于Apoptosis/Ferroptosis双重激活效应的天然产物AlbiziabiosideA的抗肿瘤作用机制研究及其结构改造
  • 批准号:
    81703335
  • 项目类别:
    青年科学基金项目
  • 资助金额:
    20.0万元
  • 批准年份:
    2017
  • 负责人:
    卫高菲
  • 依托单位:
双肝移植后Apoptosis和pyroptosis在移植物萎缩差异中的作用和供受者免疫微环境变化研究
  • 批准号:
    81670594
  • 项目类别:
    面上项目
  • 资助金额:
    58.0万元
  • 批准年份:
    2016
  • 负责人:
    陈昊
  • 依托单位:
Serp-2 调控apoptosis和pyroptosis 对肝脏缺血再灌注损伤的保护作用研究
  • 批准号:
    81470791
  • 项目类别:
    面上项目
  • 资助金额:
    73.0万元
  • 批准年份:
    2014
  • 负责人:
    董家鸿
  • 依托单位: