Targeting Muscle Fatigability During Cachexia

项目摘要/摘要 临床上，几乎所有的乳腺癌患者在诊断时和治疗前都有不同程度的 肌肉功能障碍导致疲劳，从轻微到虚弱，并可能在过程中和之后恶化 化疗、放疗和/或手术。肿瘤生长的不良全身影响通常会导致治疗 在疾病的晚期停止和更高的死亡率。我工作的长期目标是发现潜力 疲劳的治疗靶点和BC与全身肌肉疲劳的联系机制。这一行动的具体目标是 建议利用我们的小鼠模型来表征肌肉中的分子适应并识别靶点。 减轻乳腺癌患者的疲劳感。研究的中心假设是，对 通过PPARγ激动剂的线粒体生物能量学将减轻与乳腺肿瘤相关的肌肉疲劳。三 已经提出了具体的目标来验证这一假说，使用了乳腺癌的小鼠模型和新的体外实验 PPAR活性的模型。在具体目标1中，我们将检验乳腺肿瘤生长损害的工作假说。 线粒体生物能量学通过功能异常导致ATP缺乏和随后的肌肉疲劳 线粒体电子传递链(ETC)复合体V.在特定目标2中，我们将检验工作假说 乳腺肿瘤来源的miR-27A-3p与骨骼肌内PPARγ的调节成分相互作用 降低其作为转录因子的功能，从而特异性地引起线粒体功能的改变。 在特定的目标3中，将检验工作假说，即吡格列酮将减轻乳腺肿瘤相关性疲劳 通过上调骨骼肌中PPARγ的转录活性，从而拯救线粒体生物能量学 和三磷酸腺苷生产。使用和不使用吡格列酮的BC-PDOX小鼠和对照组将被评估为 肌肉疲劳、线粒体生物能量学和ATP含量。该项目在使用上具有概念上的创新性 临床前小鼠模型的表型和转录模拟BC相关的肌肉疲劳 没有恶病质。我们的方法既独特又实用，因为它寻求为 改变现有FDA批准的PPARγ激动剂的用途，直接用于治疗BC患者的疲劳 解决这一领域的关键知识差距。这个项目的结果将影响癌症的治疗- 相关疲劳，有可能为早期BC患者提供针对这种衰弱的治疗策略 恶病质发作前的症状。该项目的目的和目标反映了NCI的目标，如 在他们的使命声明中描述了，通过具体开展研究来促进科学知识 适用于广大患者，有助于提高患者的生活质量。 在癌症相关治疗完成后。

PROJECT SUMMARY/ABSTRACT Clinically, nearly all breast cancer patients at the time of diagnosis and prior to treatment have some degree of muscle dysfunction resulting in fatigue that ranges from mild to debilitating and may worsen during and after chemotherapy, radiation, and/or surgery. Adverse systemic effects of tumor growth can often result in treatment cessation and greater mortality in late stages of disease. The long-term goal of my work is to identify potential therapeutic targets for fatigue and a mechanism linking BC with systemic muscle fatigue. The specific goal of this proposal is to utilize our murine model to characterize the molecular adaptations in muscle and identify targets to attenuate fatigue in patients with breast cancer. The central research hypothesis is that regulation of mitochondrial bioenergetics via a PPARγ-agonist will attenuate breast tumor-associated muscle fatigue. Three Specific Aims have been proposed to test this hypothesis, using murine models of breast cancer and novel in vitro models of PPAR-activity. In Specific Aim 1, we will test the working hypothesis that breast tumor growth impairs mitochondrial bioenergetics resulting in ATP deficiency and subsequent muscle fatigue through aberrant function of mitochondrial electron transport chain (ETC) complex V. In Specific Aim 2, we will test the working hypothesis that breast tumor-derived miR-27a-3p interacts with regulatory components of PPARγ within skeletal muscle to decrease its function as a transcription factor, thereby specifically inducing alterations in mitochondrial function. In Specific Aim 3, will test the working hypothesis that pioglitazone will attenuate breast tumor-associated fatigue by upregulating PPARγ transcriptional activity in skeletal muscle, thereby rescuing mitochondrial bioenergetics and ATP production. BC-PDOX mice and controls treated with and without pioglitazone will be evaluated for muscle fatigue, mitochondrial bioenergetics and ATP content. This project is conceptually innovative in its use of a preclinical mouse model that phenotypically and transcriptionally mimics BC-associated muscle fatigue in the absence of cachexia. Our approach is both unique and practical in that it seeks to lay the foundation for repurposing an existing FDA-approved PPARγ-agonist for treatment of fatigue in patients with BC, directly addressing a key knowledge gap in this field. The outcomes of this project will impact the treatment of cancer- related fatigue, with the potential to offer early-stage BC-patients a treatment strategy targeting this debilitating symptom before the onset of cachexia. The aims and objectives of this project reflect the goals of the NCI, as described in their mission statement, by specifically conducting research that will advance scientific knowledge and be applicable to a large population of patients as well as helping improve patients’ quality of life during and following completion of cancer-associated therapy.