Necroptotic genes in cancer cellular response to radiation

癌细胞对辐射反应中的坏死性凋亡基因

• 批准号: 9322798
• 负责人: Chuan-Yuan Li
• 金额: $ 44.3万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-13 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9322798
• 关键词: Antineoplastic Agents; Apoptosis; Biological; Cause of Death; Cell Death; Cells; Cellular Membrane; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Event; Exposure to; Foundations; Genes; Genetic; Genetic Transcription; In Vitro; Inflammation; Intrinsic factor; Intuition; Laboratories; Lead; Malignant Neoplasms; Mediating; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Necrosis; Organ; Outcome; Patients; Phosphotransferases; Play; Production; Protein Kinase; Proteins; Public Health; Publications; RIPK1 gene; RIPK3 gene; Radiation; Radiation Tolerance; Radiation therapy; Reactive Oxygen Species; Reporting; Resistance; Role; Rupture; Signal Transduction; Stress; Swelling; TNFRSF1A gene; Technology; Tissues; Toxin; Transgenic Mice; Trauma; Treatment outcome; Tumorigenicity; Whole Organism; Xenograft procedure; base; cancer cell; cancer radiation therapy; cancer therapy; cell growth; cell injury; chemotherapeutic agent; genome editing; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; novel; radiation response; radiosensitive; response; small molecule inhibitor; tumor; tumor growth; tumorigenic

Necrosis has long been recognized as a major form of cell death after cellular exposure to radiation. Necrosis is generally thought to be a passive form of cell death caused by exposure to stress that leads to initial swelling and eventual rupturing of cellular membrane. Thus it is traditionally considered to be an unregulated form of cell death, in contrast to apoptosis, where a defined cascade of molecular events leads to programmed cell death. The discovery of necroptosis, which involves the systematic activation of select molecular factors that leads to active permeabilization of cellular membrane, indicates that necrosis could be actively regulated, similar to apoptosis. However, despite a recent surge of studies on the molecular signaling events involved in necroptosis, its role in cancer radiotherapy remains unclear. In this project, we propose to examine in the counter-intuitive hypothesis that the necroptotic factors play key roles in sustaining tumor growth and mediating tumor resistance to radiotherapy. Our hypothesis is based on recent results in our laboratory that indicated genetic deficiencies in necroptotic genes led to weakened tumorigenic abilities and increased radiation sensitivities of cancer cells. We will use state-of-the-art genome editing technologies such as CRISPR to examine the role of the necriptotic genes in tumor growth and tumor resistance to radiotherapy (Aim 1). We will also conduct studies to unveil the mechanisms through which the necroptotic factors promote tumor growth and tumor resistance to radiation (Aim 2). Finally, we will evaluate the anti-tumor efficacy of the small molecule inhibitors of the necroptotic factors alone or in combination with radiotherapy (Aim 3). Upon completion of the project, we hope to obtain a clearer picture of the role of necroptotic factors in tumor growth and tumor response to radiation therapy.

长期以来，坏死被认为是细胞暴露后细胞死亡的一种主要形式 辐射。坏死通常被认为是暴露于暴露引起的细胞死亡的一种被动形式 导致最初肿胀和最终破裂细胞膜的压力。因此 传统上被认为是细胞死亡的一种不受管制的形式，与凋亡相反， 定义的一系列分子事件导致编程细胞死亡。发现 坏死性，其中涉及系统激活的精选分子因子，导致 细胞膜的主动透气化表明坏死可以积极地 受调节，类似于凋亡。然而，尽管最近对分子进行了大量研究 涉及坏死性的信号传导事件，其在癌症放射疗法中的作用尚不清楚。 在这个项目中，我们建议在违反直觉的假设中探讨坏死性的假设 因素在维持肿瘤生长和介导肿瘤抗性方面起着关键作用 放疗。我们的假设是基于我们实验室的最新结果，该结果表明遗传 坏死基因的缺乏导致致命性能力减弱并增加了辐射 癌细胞的敏感性。我们将使用最先进的基因组编辑技术，例如 CRISPR检验死灵基因在肿瘤生长和肿瘤抗性中的作用 放疗（AIM 1）。我们还将进行研究，以揭示 坏死因子促进肿瘤的生长和对辐射的抗肿瘤耐药性（AIM 2）。最后，我们 将评估小分子抑制剂的抗肿瘤功效 单独或与放射疗法结合使用（AIM 3）。项目完成后，我们希望 清楚地了解坏死因子在肿瘤生长和肿瘤反应中的作用 放射治疗。