Cytokines and NFkappaBeta Regulation of Cancer Cachexia

细胞因子和 NFkappaBeta 对癌症恶病质的调节

• 批准号: 6866435
• 负责人: Denis C Guttridge
• 金额: $ 15.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-20 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866435
• 关键词: CHO cells; adipocytes; athymic mouse; biological signal transduction; cachexia; cell differentiation; enhancer binding protein; gene induction /repression; interferon gamma; myofibrils; neoplasm /cancer genetics; nuclear factor kappa beta; ovary neoplasms; striated muscles; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Elevated levels of the pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF), is associated with certain cancers. TNF is thought to be a major contributor of cancer cachexia, a syndrome characterized by extreme weight loss, resulting from the wasting of skeletal muscle and adipose tissues. It is estimated that a majority of cancer patients exhibit cachexia, and strikingly, nearly one third of cancer mortalities result from cachexia, rather than tumor burden. Although the effects of TNF in cancer cachexia have long been studied, to date, very few if any cytokine-inducible molecular targets have been identified that mediate skeletal muscle and fat degeneration. NF-kappaB is a transcription factor which is potently activated by TNF. Previously, we identified that NF-kappaB functions as a negative regulator of skeletal muscle differentiation. Recent results reveal that TNF-induced activation of NF-kappaB leads to the repressed expression of MyoD, a skeletal muscle-specific transcription factor considered the "master switch" in the regulation of myogenic differentiation. It was also elucidated that TNF action requires additional signaling from the IFN- gamma pathway to elicit muscle wasting and that this degenerative process is completely prevented in the absence of NF-kappaB activity. Similar to skeletal muscle, very little is known at the molecular level about how TNF induces adipose tissue wasting. Preliminary data in this proposal demonstrate that TNF-induced fat loss correlates with a loss of C/EBP-alpha, a transcription factor whose expression is known to be critical for the maintenance of mature fat. Results also show that overexpression of NF-kappaB inhibits C/EBP-alpha expression, suggesting that analogous to skeletal muscle, cytokine-induced fat wasting may be mediated through the actions of NF-kappaB by targeting a key transcription factor. The main objective of this proposal is to better understand how cytokines, signaling through NF-kappaB, regulate tissue differentiation relevant in disease conditions such as cancer cachexia. This objective will be accomplished by performing the following three aims: AIM 1 will address how cytokines TNF + IFN-gamma and NF-kappaB lead to skeletal muscle decay; AIM 2 will investigate how TNF and NF-kappaB regulate the loss of adipocyte tissue; and AIM 3 will determine the requirement of TNF + IFN-gamma and NF-kappaB in skeletal muscle wasting in vivo. The completion of these AIMS will provide insight on the potential of NF-kappaB as a therapeutic target in cancer cachexia.

描述（由申请人提供）：促炎性因子水平升高 细胞因子，肿瘤坏死因子-α（TNF），与某些 癌的 TNF被认为是癌症恶病质的主要贡献者， 消瘦症：一种以体重极度减轻为特征的综合症，由于 骨骼肌和脂肪组织。 据估计，大多数 癌症患者表现出恶病质，并且引人注目的是，近三分之一的癌症患者 恶病质而不是肿瘤负荷导致死亡。 虽然 肿瘤坏死因子在癌症恶病质中的作用已经研究了很长时间，迄今为止， 已经鉴定了任何能够介导 骨骼肌和脂肪变性。 NF-κ B是一种转录因子 其被TNF有效激活。 之前，我们发现NF-κ B 作为骨骼肌分化的负调节剂发挥作用。 最近 结果表明，TNF诱导的NF-κ B活化导致了抑制的NF-κ B表达。 MyoD是一种骨骼肌特异性转录因子， 肌原性分化调节中的“总开关”。 这是 还阐明了TNF的作用需要来自IFN-γ的额外信号传导。 伽马途径引起肌肉萎缩，这种退行性过程是 在没有NF-κ B活性的情况下被完全阻止。 类似于 骨骼肌，很少有人知道在分子水平上如何TNF 引起脂肪组织消耗。 本提案中的初步数据表明， TNF诱导的脂肪减少与C/EBP-α的减少相关， 已知其表达对转录因子的表达至关重要。 保持成熟脂肪。 结果还表明，NF-κ B的过表达， 抑制C/EBP-α表达，表明与骨骼肌类似， 尼古丁诱导的脂肪消耗可能通过NF-κ B的作用介导 通过靶向一个关键的转录因子 本提案的主要目的是 是为了更好地了解细胞因子如何通过NF-κ B信号传导， 组织分化相关的疾病状况，如癌症恶病质。 这一目标将通过实现以下三个目标来实现： AIM 1将阐述细胞因子TNF + IFN-γ和NF-κ B如何导致 骨骼肌衰退; AIM 2将研究TNF和NF-κ B如何调节 脂肪细胞组织的损失; AIM 3将决定TNF的需求 + 体内骨骼肌萎缩中的IFN-γ和NF-κ B。 完成 这些AIMS将提供关于NF-κ B作为一种 癌症恶病质的治疗靶点。