Molecular mechanism of a cellular necrotic cell death pathway

细胞坏死细胞死亡途径的分子机制

• 批准号: 7633055
• 负责人: JUNYING YUAN
• 金额: $ 35万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633055
• 关键词: Acute; Apoptosis; Apoptotic; Attention; Back; Caspase; Cell Death; Cells; Cessation of life; DNA Damage; Data; Family; Family member; Genes; Lead; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Methods; Mitochondria; Molecular; Mutation; Necrosis; Pathologic; Pathology; Pathway interactions; Phosphotransferases; Play; Process; Proteins; Receptor Activation; Role; Series; Signal Transduction; Small Interfering RNA; Stimulus; Stress; Therapeutic Intervention; Tumor Suppressor Proteins; Virus Diseases; cell type; genome-wide; human disease; inhibitor/antagonist; insight; member; novel; outcome forecast; receptor; response; small molecule

The objective of this proposal is to study the molecular mechanism of necroptosis, a cellular necrotic cell death pathway. Apoptosis has been established as a cellular mechanism that regulates programmed cell death. However, it has become increasingly clear that apoptosis is not the only cellular mechanism that regulates cell death. Apoptosis triggered by the activation of death receptors represents a prototypic apoptosis pathway. Interestingly, stimulation of certain apoptotic deficient cells with death receptor ligands such as FasL or TNFα has been shown to lead to necrotic cell death termed necroptosis. Cell death with necrotic features (necrosis) is prevalent in cancers, viral infections and other acute pathologies. Furthermore, excessive necrosis in cancers has long been noted as a indicator for poor prognosis. However, very little attention has been directed towards studying necrosis because necrosis is believed to be an unregulated process caused by overwhelming external stress. The discovery of necroptosis offers the possibility that a subset of pathologic necrotic cell death is regulated by a distinct cellular mechanism, and therefore is amenable to therapeutic intervention. A genome-wide siRNA screen of 16,873 genes was carried out to identify genes involved in regulating necroptosis. A set of genes was identified as common mediators of necroptosis that are downstream of RIP1, an essential kinase for the activation of necroptosis. This screen identified a tumor suppressor network previously known to regulate DNA damage response and a BH3-only member of Bcl-2 family in the signaling of necroptosis. This proposal is to characterize the role of necroptosis and RIPI kinase in DFJA damage induced cell death and to determine the mechanism by which RIPI mediates the activation of BH3-only Bcl-2 family member in the execution of necroptosis. This study will provide important molecular insights into a cellular necrotic cell death pathway. Understanding the mechanism by which cells regulate necroptotic cell death may provide unique opportunities for developing novel therapies of major human diseases with little or no known treatment.

本提案的目的是研究坏死性凋亡（一种细胞坏死性细胞死亡途径）的分子机制。细胞凋亡已被确立为调节程序性细胞死亡的细胞机制。 然而，越来越清楚的是，细胞凋亡不是调节细胞死亡的唯一细胞机制。由死亡受体的激活触发的细胞凋亡代表了原型细胞凋亡途径。有趣的是，用死亡受体配体如FasL或TNFα刺激某些凋亡缺陷细胞已显示导致坏死性细胞死亡，称为坏死性凋亡。具有坏死特征的细胞死亡（坏死）在癌症、病毒感染和其他急性病理中普遍存在。此外，癌症中的过度坏死长期以来被认为是预后不良的指标。然而，很少有人注意到研究坏死，因为坏死被认为是一个不受调节的过程所造成的压倒性的外部压力。坏死性凋亡的发现提供了一种可能性，即病理性坏死细胞死亡的一个子集是由一种独特的细胞机制调节的，因此可以进行治疗干预。 对16，873个基因进行全基因组siRNA筛选以鉴定参与调节坏死性凋亡的基因。一组基因被鉴定为坏死性凋亡的常见介质，其位于RIP 1的下游，RIP 1是激活坏死性凋亡的必需激酶。该筛选鉴定了先前已知调节DNA损伤反应的肿瘤抑制网络和在坏死性凋亡信号传导中的Bcl-2家族的仅BH 3成员。本研究拟探讨坏死性凋亡和里皮激酶在DFJA损伤诱导的细胞死亡中的作用，并探讨里皮激酶介导BH 3-only Bcl-2家族成员活化的机制。这项研究将为细胞坏死细胞死亡途径提供重要的分子见解。了解细胞调节坏死性细胞死亡的机制可能为开发新的治疗方法提供独特的机会，这些方法用于治疗人类主要疾病，而治疗方法很少或根本没有。