TTUMOR NECROSIS FACTOR ACTION IN CELLS

肿瘤坏死因子在细胞中的作用

• 批准号: 6150202
• 负责人: DAVID B DONNER
• 金额: $ 24.19万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6150202
• 关键词: apoptosis; biological signal transduction; cell proliferation; cytokine receptors; enzyme activity; mitogen activated protein kinase; phosphates; protein structure function; tumor necrosis factor alpha

THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OR AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEND ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE ABSTRACT BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. DESCRIPTION: The long-term objective of the proposed research is to develop an understanding of how tumor necrosis factor (TNF) promotes its biological effects in its target cells. TNF is a cytokine with potential for the treatment of cancer that also promotes immunity, anti- viral responses, metabolic changes that accompany various diseases, the insulin-resistance of non-insulin dependent diabetes and inflammatory processes, including those that lead to arthritis. To promote the potential of TNF as a therapeutic agent and to abrogate its pathological activities requires insight into the mechanisms of TNF action. Two different TNF receptors promote cellular responses but neither contains intrinsic tyrosine kinase activity nor any motif that suggests how a signal is transmitted into the cell. Receptors without tyrosine kinase activity often bind accessory proteins that mediate interactions with signaling cascades thereby promoting biological responses. However, genes for TNF receptor-associated proteins (TRAPS) and the sequences of the proteins that they encode have not been previously identified and this may be the most significant gap in our understanding of how TNF brings about its effects. The applicant has used the yeast based two- hybrid system to discover three potentially novel genes that encode TRAPS. By analyzing which cellular responses are promoted by each TRAP, and by characterizing how TRAPS mediate signal transduction, the applicant hopes to gain fundamental insight into the molecular basis for TNF action. To accomplish this goal, the applicant will overexpress each TRAP or TRAP antisense in cells from which TNF elicits diverse responses. Control and TNF-stimulated cells will then be assayed for activation of various second messenger systems and cellular responses, such as cytotoxicity and activation of NF-kappaB.

这是一个香农奖提供部分支持的研究 项目不属于指定机构的资助范围，但 在优秀的边缘。香农奖旨在提供 支持测试方法的可行性;支持进一步测试 和完善研究技术;进行二次分析或提供 数据集;或进行离散项目，以证明PI 研究能力或为已经优秀的 应用程序.以下摘要摘自原始文件 由主要经销商提交。 描述：拟议研究的长期目标是 了解肿瘤坏死因子（TNF）如何促进其 对靶细胞的生物学效应。 TNF是一种细胞因子， 治疗癌症的潜力，也促进免疫力，抗- 病毒反应，伴随各种疾病的代谢变化， 非胰岛素依赖型糖尿病胰岛素抵抗与炎症 过程，包括那些导致关节炎。 推进 TNF作为治疗剂的潜力和消除其病理性 活动需要深入了解TNF的作用机制。 两 不同的TNF受体促进细胞反应，但都不包含 内在酪氨酸激酶活性，也没有任何基序，表明如何 信号被传送到细胞中。 无酪氨酸激酶受体 活性通常结合辅助蛋白，辅助蛋白介导与 信号级联从而促进生物反应。 然而，在这方面， TNF受体相关蛋白（TRAPS）的基因和 它们编码的蛋白质以前没有被鉴定过， 这可能是我们理解TNF如何 带来了它的影响。 申请人已经使用了基于酵母的两种- 杂交系统发现三个潜在的新基因， 阱. 通过分析每个TRAP促进哪些细胞反应， 并通过表征TRAPS如何介导信号转导， 申请人希望获得对分子基础的基本了解， TNF作用。 为了实现这一目标，申请人将过度表达 在TNF诱导分化的细胞中的每个TRAP或TRAP反义 应答 然后测定对照和TNF刺激的细胞的 各种第二信使系统和细胞反应的激活， 如细胞毒性和NF-κ B活化。