TTUMOR NECROSIS FACTOR ACTION IN CELLS

这是香农奖，为这项研究提供部分支持 项目低于指定研究所的资助范围，但 都在最优秀的边缘。香农奖旨在提供 支持测试该方法的可行性；开发进一步的测试 并改进研究方法；进行二次分析或可用 数据集；或执行可演示PI的离散项目 研究能力或为已经功成名就的 申请。下面的摘要摘自原始文件 由首席调查员提交。 描述：拟议研究的长期目标是 了解肿瘤坏死因子(TNF)是如何促进其 其靶细胞的生物学效应。肿瘤坏死因子是一种与 治疗癌症的潜力也可以提高免疫力，抗- 病毒反应，伴随着各种疾病的代谢变化， 非胰岛素依赖型糖尿病与炎症的胰岛素抵抗 过程，包括那些导致关节炎的过程。为了促进 肿瘤坏死因子作为治疗剂的潜力及其病理基础 这些活动需要深入了解肿瘤坏死因子的作用机制。二 不同的肿瘤坏死因子受体促进细胞反应，但都不包含 固有的酪氨酸激酶活性也不是任何暗示 信号被传输到细胞内。不含酪氨酸激酶的受体 活性经常与辅助蛋白结合，这些辅助蛋白介导与 信号级联，从而促进生物反应。然而， 肿瘤坏死因子受体相关蛋白(TRAP)基因及其序列 它们编码的蛋白质以前没有被鉴定过，而且 这可能是我们对肿瘤坏死因子如何 带来了它的影响。申请人已经使用了基于两种酵母的- 混合系统发现三个潜在的编码新基因 陷阱。通过分析每个陷阱促进了哪些细胞反应， 通过描述陷阱是如何调节信号转导的， 申请者希望对分子基础有基本的了解 肿瘤坏死因子作用。为了实现这一目标，申请者将过度表达 每个陷阱或陷阱在细胞中反义产生不同的肿瘤坏死因子 回应。然后检测对照细胞和肿瘤坏死因子刺激的细胞 激活各种第二信使系统和细胞反应， 如核因子-kappaB的细胞毒性和激活。

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.