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.

项目总结/文摘