Pro-oncogenic roles of apoptotic caspases

凋亡半胱天冬酶的促癌作用

• 批准号: 9230369
• 负责人: Chuan-Yuan Li
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-08 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230369
• 关键词: Apoptosis; Apoptotic; CASP3 gene; CASP7 gene; Cancer Etiology; Caspase; Cell Death; Cells; Chemicals; DNA Damage; Evaluation; Exposure to; Future; Genetic; Genomic Instability; Goals; Human; In Vitro; Ionizing radiation; Laboratories; Lead; MYC gene; Malignant - descriptor; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutagenesis; Oncogenes; Oncogenic; Outcome; Play; Prevention strategy; Process; Public Health; Publishing; Radiation; Role; Stimulus; Stress; Technology; base; cancer prevention; carcinogenesis; carcinogenicity; cell injury; endonuclease G; genetic approach; in vivo; in vivo Model; insight; novel; public health relevance

DESCRIPTION (provided by applicant): Apoptosis is normally considered a barrier for carcinogenesis because of its roles in getting rid of unwanted or damaged cells. However recent discoveries in our laboratory suggest that we need to re-examine the roles of apoptosis, especially those of apoptotic caspases, in carcinogenesis. In this project, we will examine the hypothesis that non-lethal caspase 3 or 7 activation induces genomic instability to facilitate radiation and other stress-induced carcinogenesis. Our hypothesis is a bold one that goes against the current paradigm. It will have wide-ranging implications since many endogenous and external stimuli could activate apoptotic caspases. Examples of such stimuli include exposure to ionizing radiation, UV, chemicals, and oncogene expression (e.g., myc). A facilitative role for caspases in carcinogenesis would provide exciting new insights into how those diverse environmental insults cause cancer. We will use a variety of in vitro and in vivo models, in combination with state-of-the-art molecular technologies, to examine the roles of caspases 3&7 in radiation- and other stress-induced genetic instability and carcinogenesis. We expect our studies to provide a comprehensive evaluation of the roles of caspases 3&7 in promoting carcinogenesis through inducing genetic instability. Upon completion of the project, we hope we can gain significant insights into the roles of apoptotic caspases in carcinogenesis. Such insights may provide novel targets for future cancer prevention strategies.

描述（由申请人提供）：细胞凋亡通常被认为是致癌的障碍，因为它在消除不需要的或受损的细胞方面发挥着作用。然而，我们实验室最近的发现表明，我们需要重新审视细胞凋亡，尤其是凋亡半胱天冬酶在癌发生中的作用。在这个项目中，我们将检验以下假设：非致命性 caspase 3 或 7 激活会诱导基因组不稳定，从而促进辐射和其他应激诱导的致癌作用。我们的假设是一个大胆的假设，与当前的范式背道而驰。它将具有广泛的影响，因为许多内源性和外部刺激可以激活凋亡半胱天冬酶。此类刺激的例子包括暴露于电离辐射、紫外线、化学品和癌基因表达（例如 myc）。半胱天冬酶在致癌作用中的促进作用将为了解这些不同的环境损害如何导致癌症提供令人兴奋的新见解。我们将使用各种体外和体内模型，结合最先进的分子技术，研究 caspase 3 和 7 在辐射和其他应激诱导的遗传不稳定性和致癌作用中的作用。我们希望我们的研究能够全面评估 caspase 3 和 7 通过诱导遗传不稳定性促进癌发生的作用。该项目完成后，我们希望能够深入了解凋亡半胱天冬酶在致癌过程中的作用。这些见解可能为未来的癌症预防策略提供新的目标。