FoxO signaling and skeletal muscle atrophy

项目摘要/摘要 恶病质的特征是进行性的骨骼肌和体重减轻，影响多达80%的 癌症患者。由于这种肌肉质量的丧失会导致虚弱，因此降低了对常规 治疗和增加死亡率，了解导致肌肉萎缩的机制对于 开发治疗方法，以提高癌症患者的生活质量和生存能力。出版并出版 我们实验室未公布的数据表明，Forkhead Box(Fox)O类蛋白FoxO1是一个关键的 与癌症患者恶病质相关的肌肉损耗调节因子。我们鉴定了转录的 抑制子FoxP1作为FoxO1上调肿瘤负荷(TBU)的靶基因 在恶病质癌肌肉萎缩和平行肌肉萎缩之前的时间点上，也是增加的 病人。在初步实验中，我们发现FoxP1a)可能是一个有效的关键转录抑制因子 涉及肌肉收缩和维持肌肉完整性的因素和基因，b)足以 诱导肌纤维萎缩和c)是TBU诱导的肌纤维萎缩所必需的，从而涉及FoxP1 在恶病质表型中。因此，目标1和目标2将测试我们的基本假设，即FoxP1是足够的 导致肌肉超微结构恶化，分解代谢途径激活，肌肉萎缩 在这些肿瘤引起的肌肉病理中，TbU引起的肌肉虚弱和其上调是必需的。 具体目标1：我们将确定FoxP1的作用并研究其分子机制 足以导致肌肉萎缩。具体目标2：确定角色并调查 FoxO1-FoxP1-MEF2C轴驱动癌症引起的肌肉萎缩的机制。我们将测试 这些假说在传统的临床前恶病质小鼠模型中以及在一种新的小鼠恶病质模型中 胰腺导管腺癌(PDAC)患者直接切除肿瘤的癌性恶病质 附着在免疫受损小鼠的胰腺上，创造出小鼠的化身。 特定目标3：确定体重骨骼肌转录组和蛋白质组的变化 在癌症恶病质进展过程中失去PDAC患者和他们的小鼠化身。我们的第三个目标 利用我们广泛接触PDAC患者的肌肉和肿瘤组织的优势。因此，我们提出了一个 无偏方法鉴定PDAC肌肉转录组(通过RNA-SEQ)和蛋白质组(通过iTRAQ) 患者及其在恶病质进展过程中的小鼠化身作为纵向疾病的替代 在人体上的研究。我们建议用肌肉组织学和超微结构来补充这些发现。 我们预计，我们在目标1和目标2中的发现将阐明 对TBU的回应，而AIM 3中产生的数据将产生过多的新知识，以指导未来的Pre 临床和临床研究，旨在预防或延缓癌症引起的恶病质在人类条件下。

Project Summary/Abstract Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients. Published and unpublished data from our lab have identified the Forkhead Box (Fox) Class O protein, FoxO1, as a critical regulator of muscle wasting that is associated with cachexia in cancer patients. We identified the transcriptional repressor, FoxP1, as a target gene upregulated by FoxO1 in response to tumor burden (TBu) that is increased at time points which precede and parallel muscle wasting and is also increased in muscle of cachectic cancer patients. In preliminary experiments we found that FoxP1 a) may act as a potent repressor of key transcription factors and genes involved in muscle contraction and the maintenance of muscle integrity, b) is sufficient to induce muscle fiber atrophy and c) is required for muscle fiber atrophy induced by TBu, thus implicating FoxP1 in the cachectic phenotype. Aims 1 and 2 will therefore test our underlying hypothesis that FoxP1 is sufficient to induce deterioration of muscle ultrastructure, activation of catabolic pathways, and muscle atrophy and weakness and that its upregulation in response to TBu is required for these tumor-induced muscle pathologies. Specific Aim 1: We will establish the role and investigate the molecular mechanisms by which FoxP1 is sufficient to induce muscle wasting. Specific Aim 2: To establish the role and investigate the mechanisms by which a FoxO1-FoxP1-MEF2c axis drives cancer-induced muscle wasting. We will test these hypotheses in a conventional pre-clinical mouse model of cachexia as well as in a novel mouse model of cancer cachexia in which primary resected tumors from pancreatic ductal adenocarcinoma (PDAC) patients are attached to the pancreas of immunocompromised mice to create mouse avatars. Specific Aim 3: To identify changes in the skeletal muscle transcriptome and proteome of weight losing PDAC patients and their mouse avatars during the progression of cancer cachexia. Our third aim takes advantage of our wide access to muscle and tumor tissue from PDAC patients. We thus propose an unbiased approach to identify the transcriptome (via RNA-seq) and proteome (via iTRAQ) in muscle of PDAC patients as well as their mouse avatars during the progression of cachexia as a surrogate for longitudinal studies in humans. We propose to complement these findings with muscle histology and ultrastructure. We anticipate that our findings from Aims 1 and 2 will elucidate key mechanisms of wasting and weakness in response to TBu, while data generated in Aim 3 will generate a plethora of new knowledge to guide future pre- clinical and clinical studies aimed at preventing or retarding cancer-induced cachexia in the human condition.