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: 10089416
• 负责人: Fang 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 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089416
• 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; efficacy evaluation; genome editing; in vivo; inhibitor/antagonist; insight; mouse model; neoplastic cell; novel; radiation response; 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于环境中后细胞死亡的主要形式。 辐射坏死通常被认为是一种被动形式的细胞死亡所造成的暴露于 导致细胞膜最初膨胀并最终破裂的应力。因此 传统上被认为是一种不受调节的细胞死亡形式，与细胞凋亡相反， 一系列明确的分子事件导致程序性细胞死亡。的发现 坏死性凋亡，它涉及选择的分子因子的系统激活，导致 细胞膜的活性透化，表明坏死可能是积极的， 类似于凋亡。然而，尽管最近对分子生物学的研究 尽管参与坏死性凋亡的信号传导事件，其在癌症放射治疗中的作用仍不清楚。 在这个项目中，我们提出了一个反直觉的假设，即坏死性下垂， 因子在维持肿瘤生长和介导肿瘤抵抗中起关键作用。 放疗我们的假设是基于我们实验室的最新结果， 坏死性凋亡基因的缺陷导致肿瘤发生能力减弱和辐射增加 癌细胞的敏感性。我们将使用最先进的基因组编辑技术， CRISPR检测了坏死基因在肿瘤生长和肿瘤耐药性中的作用。 放疗（目标1）。我们亦会进行研究，以揭示 坏死因子促进肿瘤生长和肿瘤对辐射的抵抗（目的2）。最后我们 将评估坏死性凋亡因子的小分子抑制剂的抗肿瘤功效 单独或与放射疗法组合（Aim 3）。项目完成后，我们希望 更清楚地了解坏死性凋亡因子在肿瘤生长和肿瘤对 放射治疗