Molecular mechanisms of death in cells with defective apoptotic pathways

凋亡途径缺陷细胞死亡的分子机制

• 批准号: nhmrc : 454506
• 负责人: A/Pr Nigel Waterhouse
• 金额: $ 22.34万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/molecular-mechanisms-death-apoptotic-pathways/95670
• 关键词: Molecular; mechanisms; death; cells; defective

The body protects itself from cancer by killing any cell that poses a risk of becoming a tumour. The body kills these cells via a carefully orchestrated sequence (or pathway) of events, however many cancer cells have defects in cell death pathways that has permitted them to survive even though they have been told to die. In this proposal we set out a research program to investigate how to kill cancer cells that don't want to die. Various tumour cells have been shown to have increased levels of Bcl-2, a proto-oncogene that blocks cell death induced by diverse stimuli. Cells that over-express Bcl-2 are also resistant to cytotoxic drugs. Understanding how to bypass Bcl-2 (or proteins that block cell death in tumours) will lead to a better understanding of cell death-cell survival and allow us to explore the possibility of tailoring treatment for patients in which specific defects in death pathways have been identified in their cancer cells. Cytotoxic lymphocytes (CL) are cells of the immune system that defend the body from cancer by specifically attacking and killing tumor cells. We have been pioneering studies of CL:tumour interactions in which we can define the morphology and kinetics of critical events in cell death and have shown that CL have the ability to kill target cells that over-express Bcl-2. Following the aims in this proposal, we will understand the mechanisms by which cytotoxic lymphocytes kill target cells that have defects in classical cell death pathways. These studies will therefore define alternative pathways to cell death in the event that a key component of the preferential pathway to cell death is inoperative. Since cytotoxic lymphocytes use a variety of ways to kill their targets and tumors may contain multiple defects in cell death pathways, we will explore which are the key defects, or the combination of multiple defects, in cell death pathways that prevent cytotoxic lymphocyte mediated cell death and permit tumour survival in vivo.

人体通过杀死任何有可能成为肿瘤的细胞来保护自己免受癌症的侵袭。人体通过精心安排的一系列事件来杀死这些细胞，然而许多癌细胞在细胞死亡途径上存在缺陷，这使得它们能够存活下来，尽管它们被告知要死亡。在这项提案中，我们制定了一个研究计划，以调查如何杀死不想死亡的癌细胞。各种肿瘤细胞已被证明具有增加的水平的Bcl-2，这是一种原癌基因，阻止细胞死亡由不同的刺激。过度表达Bcl-2的细胞也对细胞毒药物产生抗药性。了解如何绕过Bcl-2(或阻止肿瘤中细胞死亡的蛋白质)将有助于更好地了解细胞死亡-细胞存活，并使我们能够探索为癌症细胞中发现特定死亡途径缺陷的患者量身定做治疗的可能性。细胞毒性淋巴细胞(CL)是免疫系统中的细胞，通过特异性地攻击和杀死肿瘤细胞来保护身体免受癌症的侵袭。我们一直在对CL：肿瘤相互作用进行开创性的研究，在这些研究中，我们可以定义细胞死亡中关键事件的形态和动力学，并表明CL具有杀死过度表达Bcl-2的靶细胞的能力。按照这一建议的目标，我们将了解细胞毒性淋巴细胞杀死在经典细胞死亡途径中存在缺陷的靶细胞的机制。因此，这些研究将确定在优先细胞死亡途径的一个关键组成部分不起作用的情况下细胞死亡的替代途径。由于细胞毒淋巴细胞可通过多种方式杀伤靶细胞，而肿瘤细胞死亡途径中可能存在多种缺陷，我们将探讨哪些是细胞死亡途径中的关键缺陷，或多种缺陷的组合，以防止细胞毒性淋巴细胞介导的细胞死亡，并允许肿瘤在体内存活。