Targeting Muscle Fatigability During Cachexia

针对恶病质期间的肌肉疲劳

• 批准号: 10634731
• 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/10634731
• 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 gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Physiological; Pioglitazone; Porifera; Production; Quality of life; 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; 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.

项目摘要/摘要 临床上，诊断时几乎所有乳腺癌患者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，可能在 化学疗法，放射和/或手术。肿瘤生长的不良全身影响通常会导致治疗 疾病晚期停止和更大的死亡率。我工作的长期目标是确定潜力 疲劳的治疗靶标和将BC与全身肌肉疲劳联系起来的机制。这个的具体目标 建议是利用我们的鼠模型来表征肌肉中的分子适应并识别靶标 减轻乳腺癌患者的疲劳。中心研究假设是调节 通过PPARγ激动剂的线粒体生物能力会减弱与乳腺肿瘤相关的肌肉疲劳。三 已经提出了使用乳腺癌的鼠模型和新颖的体外模型来检验该假设的具体目的 PPAR活动模型。在特定目标1中，我们将测试乳腺肿瘤生长损害的工作假设 线粒体生物能力导致ATP缺乏和随后通过异常功能的肌肉疲劳 线粒体电子传输链（ETC）复合物V。在特定目标2中，我们将测试工作假设 乳腺肿瘤衍生的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，从而特别诱导线粒体功能的改变。 在特定目标3中，将检验吡格列酮会减弱乳腺肿瘤相关的疲劳的工作假设 通过上调骨骼肌中的PPARγ转录活性，从而营救线粒体生物能 和ATP生产。 BC-PDOX小鼠和接受和没有吡格列酮处理的对照将评估 肌肉疲劳，线粒体生物能和ATP含量。该项目在概念上是创新的 在表型和转录模仿BC相关的肌肉疲劳的临床前小鼠模型中 缺乏卡希克西亚。我们的方法既独特又实用，因为它试图为 重新利用现有的FDA批准的PPARγ激动剂，以治疗BC患者的疲劳，直接 解决该领域的关键知识差距。该项目的结果将影响癌症的治疗 相关的疲劳，有可能提供早期BC患者的治疗策略，以此为目标 症状在恶病质发作前。该项目的目的和目标反映了NCI的目标， 在他们的使命陈述中描述的，专门进行研究，以提高科学知识 并适用于大量患者，并帮助改善患者的生活质量和 完成癌症相关治疗后。