Cytokines and NFkappaBeta Regulation of Cancer Cachexia

描述(由申请人提供)：促炎因子水平升高 细胞因子，肿瘤坏死因子-α(TNF)，与某些 癌症。肿瘤坏死因子被认为是癌症恶病质的主要贡献者， 一种综合症，其特征是体重极度减轻，这是由于浪费了 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，近三分之一的癌症患者 死亡是恶病质造成的，而不是肿瘤负担。尽管 肿瘤坏死因子在癌症恶病质中的作用已经被研究很久了，到目前为止，很少有人 任何细胞因子诱导的分子靶点都已被确定为介导 骨骼肌和脂肪变性。核因子-kappaB是一种转录因子 它被肿瘤坏死因子有效地激活。此前，我们发现核因子-kappaB 对骨骼肌的分化起负调节作用。近期 结果表明，肿瘤坏死因子诱导的核因子-kappaB的激活导致抑制 骨骼肌特异性转录因子MyoD的表达 肌源性分化调控中的“总开关”。确实是 还阐明了肿瘤坏死因子的作用需要干扰素的额外信号。 伽马途径导致肌肉萎缩，这种退化过程是 在缺乏核因子-kappaB活性的情况下，完全可以预防。类似于 骨骼肌，在分子水平上对肿瘤坏死因子如何 会导致脂肪组织的浪费。这份提案中的初步数据表明 肿瘤坏死因子诱导的脂肪减少与C/EBP-α、a 转录因子，其表达被认为是对 维持成熟脂肪。结果还表明，核因子-kappaB的过度表达 抑制C/EBP-α的表达，表明类似于骨骼肌， 细胞因子诱导的脂肪消耗可能是通过核因子-kappaB的作用介导的 通过靶向一个关键的转录因子。这项提案的主要目的是 是为了更好地了解细胞因子是如何通过核因子-kappaB信号调节 组织分化与癌症恶病质等疾病相关。 这一目标将通过实现以下三个目标来实现： 目标1将解决细胞因子肿瘤坏死因子+干扰素-γ和核因子-kappaB如何导致 骨骼肌衰退；AIM 2将研究肿瘤坏死因子和核因子-kappaB如何调节 脂肪组织的丢失；AIM 3将决定对肿瘤坏死因子的需求 +干扰素-γ和核因子-kappaB在体内骨骼肌萎缩中的作用。完成度 将提供对核因子-kappaB作为一种 癌症恶病质的治疗靶点。

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.