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）：促炎的水平升高 细胞因子，肿瘤坏死因子-Alpha（TNF）与某些人有关 癌症。 TNF被认为是癌症恶病质的主要因素，一个 综合征以极端体重减轻的特征，导致浪费 骨骼肌和脂肪组织。 据估计，大多数 癌症患者表现出恶病质，令人惊讶的是，近三分之一的癌症 死亡的死亡率是由于恶病质而不是肿瘤负担。 虽然 迄今为止 已经确定了任何细胞因子诱导的分子靶标，可以介导 骨骼肌和脂肪变性。 NF-kappab是转录因子 这是由TNF有效激活的。 以前，我们确定了NF-kappab 充当骨骼肌分化的负调节剂。 最近的 结果表明，TNF诱导的NF-kappab激活导致抑制 MYOD的表达，考虑到骨骼肌肉特异性转录因子 肌原分化调节中的“主开关”。 是 还阐明了TNF作用需要从IFN- 伽马引起肌肉浪费的途径，这种退化过程是 在没有NF-kappab活动的情况下，完全阻止了。 类似于 骨骼肌，在分子水平上几乎没有关于TNF的知名度 诱导脂肪组织浪费。 此提案中的初步数据证明 TNF诱导的脂肪流失与C/EBP-Alpha的损失相关，A 转录因子的表达因素对 维持成熟的脂肪。 结果还表明NF-kappab的过表达 抑制C/EBP-Alpha表达，表明类似于骨骼肌肉， 细胞因子诱导的脂肪浪费可以通过NF-kappab的作用介导 通过靶向关键转录因子。 该提议的主要目标 是为了更好地了解细胞因子如何通过NF-kappab发出信号，调节 在疾病状况（例如癌症恶病质）中相关的组织分化。 该目标将通过执行以下三个目标来实现： AIM 1将解决细胞因子TNF + IFN-GAMMA和NF-kappab如何导致 骨骼肌衰减； AIM 2将调查TNF和NF-kappab如何调节 脂肪细胞组织的丧失； AIM 3将确定TNF的要求 +体内骨骼肌浪费的IFN-gamma和NF-kappab。 完成 这些目标中将提供有关NF-kappab作为一个潜力的见解 癌症恶病质的治疗靶标。