Targeting Muscle Fatigability During Cachexia

项目总结/摘要 在临床上，几乎所有的乳腺癌患者在诊断时和治疗前都有一定程度的 肌肉功能障碍导致疲劳，范围从轻度到衰弱，并可能在治疗期间和治疗后恶化 化疗、放疗和/或手术。肿瘤生长的不良全身效应通常会导致治疗 疾病晚期的停止和更高的死亡率。我工作的长期目标是找出潜在的 疲劳的治疗靶点以及将BC与全身性肌肉疲劳联系起来的机制。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。中心研究假设是， 通过PPARγ-激动剂的线粒体生物能量学将减弱乳腺肿瘤相关的肌肉疲劳。三 已经提出了具体的目的来测试这一假设，使用乳腺癌的小鼠模型和新的体外研究。 PPAR-activity模型。在具体目标1中，我们将测试乳腺肿瘤生长损害 线粒体生物能量学导致ATP缺乏和随后的肌肉疲劳通过异常功能 线粒体电子传递链（ETC）复合物V。在具体目标2中，我们将测试工作假设 乳腺肿瘤来源的miR-27 a-3 p与骨骼肌内的PPARγ调节组分相互作用， 降低其作为转录因子的功能，从而特异性地诱导线粒体功能的改变。 在具体目标3中，将检验吡格列酮将减轻乳腺肿瘤相关疲劳的工作假设 通过上调骨骼肌中的PPARγ转录活性， ATP的生产。将评价接受和不接受吡格列酮治疗的BC-PDOX小鼠和对照组的以下指标： 肌肉疲劳、线粒体生物能量学和ATP含量。这个项目在概念上是创新的使用 临床前小鼠模型，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，因为它寻求为以下方面奠定基础： 将现有的FDA批准的PPARγ激动剂用于治疗BC患者的疲劳， 填补这一领域的关键知识空白。该项目的成果将影响癌症的治疗- 相关的疲劳，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国家癌症研究所的目标， 在他们的使命声明中描述，通过专门进行研究，将促进科学知识 并且适用于大量患者，以及帮助改善患者在治疗期间和治疗期间的生活质量。 完成癌症相关治疗后。

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.