Targeting Muscle Fatigability During Cachexia

针对恶病质期间的肌肉疲劳

• 批准号: 10445436
• 负责人: Emidio Edward Pistilli
• 金额: $ 33.44万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-03 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10445436
• 关键词: Address; Affect; Agonist; American Cancer Society; Animal Model; Attenuated; Bioenergetics; Body Weight decreased; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; Cachexia; Cancer Patient; Chemotherapy and/or radiation; Clinical; Clinical Research; Defect; Diabetes Mellitus; Diagnosis; Disease; Down-Regulation; Electron Transport; FDA approved; Fatigue; Foundations; Functional disorder; Future; Gene Expression Profile; Genetic Transcription; Goals; Human; Impairment; Knowledge; Laboratories; Link; Mammary Neoplasms; Measures; Mediating; Metabolic; MicroRNAs; Mission; Mitochondria; Modeling; Molecular; Mus; Muscle; Muscle Contraction; Muscle Fatigue; Muscle Fibers; Muscle Mitochondria; Muscular Atrophy; Operative Surgical Procedures; Outcome; PPAR alpha; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physiological; Pioglitazone; Porifera; Production; Quality of life; Radiation therapy; Regulation; Reporting; Research; Scientific Advances and Accomplishments; Signal Transduction; Skeletal Muscle; Testing; Therapeutic; Time; Treatment-Related Cancer; Tumor-Derived; Withholding Treatment; Work; Xenograft procedure; cancer diagnosis; chemotherapy; clinically relevant; disabling symptom; experience; experimental study; improved; in vitro Model; innovation; malignant breast neoplasm; mimetics; mitochondrial dysfunction; molecular subtypes; mortality; mouse model; muscle form; novel; oligomycin sensitivity-conferring protein; patient population; pre-clinical; response; stem; targeted treatment; therapeutic target; transcription factor; treatment strategy; tumor growth

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.

项目概要/摘要 临床上，几乎所有乳腺癌患者在诊断时和治疗前都存在一定程度的 肌肉功能障碍导致疲劳，程度从轻度到虚弱，并且可能在期间和之后恶化 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 疾病晚期停止和更高的死亡率。我工作的长期目标是发现潜力 疲劳的治疗目标以及将 BC 与全身肌肉疲劳联系起来的机制。此次活动的具体目标 建议利用我们的小鼠模型来表征肌肉的分子适应并确定目标 减轻乳腺癌患者的疲劳。中心研究假设是监管 通过 PPARγ 激动剂的线粒体生物能量学将减轻乳腺肿瘤相关的肌肉疲劳。三 已经提出了使用乳腺癌小鼠模型和新型体外模型来检验这一假设的具体目标 PPAR 活性模型。在具体目标 1 中，我们将检验乳腺肿瘤生长损害的工作假设 线粒体生物能量学导致 ATP 缺乏，并通过功能异常导致随后的肌肉疲劳 线粒体电子传递链 (ETC) 复合体 V 的结构。在具体目标 2 中，我们将测试工作假设 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，从而特异性诱导线粒体功能的改变。 在具体目标 3 中，将检验吡格列酮可减轻乳腺肿瘤相关疲劳的工作假设 通过上调骨骼肌中 PPARγ 转录活性，从而拯救线粒体生物能 和 ATP 生产。将评估用或不用吡格列酮治疗的 BC-PDOX 小鼠和对照 肌肉疲劳、线粒体生物能学和 ATP 含量。该项目在概念上具有创新性 临床前小鼠模型的表型和转录模拟 BC 相关肌肉疲劳 没有恶病质。我们的方法既独特又实用，旨在为以下方面奠定基础： 将 FDA 批准的现有 PPARγ 激动剂重新利用，直接用于治疗 BC 患者的疲劳 解决该领域的关键知识差距。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症状的治疗策略 恶病质发作前的症状。该项目的宗旨和目标反映了 NCI 的目标： 在他们的使命宣言中描述，通过专门开展研究来推进科学知识 适用于大量患者，有助于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。