Targeting Muscle Fatigability During Cachexia

针对恶病质期间的肌肉疲劳

基本信息

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
项目类别：
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

项目摘要

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/或手术对肿瘤生长的不良全身影响通常会导致治疗。疾病晚期的戒烟和更高的死亡率我工作的长期目标是确定潜在的风险。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。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的中心研究假设是调节通过 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。已经提出了具体目标来检验这一假设，使用乳腺癌小鼠模型和新型体外在特定目标 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将评估用或不用吡格列酮治疗的 BC-PDOX 小鼠和对照小鼠的 ATP 产生。该项目在概念上具有创新性，包括肌肉疲劳、线粒体生物能学和 ATP 含量。临床前小鼠模型的表型和转录模拟 BC 相关肌肉疲劳我们的方法既独特又实用，旨在为消除恶病质奠定基础。将 FDA 批准的现有 PPARγ 激动剂重新利用，直接用于治疗 BC 患者的疲劳该项目的成果将解决该领域的关键知识差距，从而影响癌症的治疗。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该项目的目的和目标反映了 NCI 的目标，即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。