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(PQ 12) The Regulation of Physical Function and Skeletal Muscle Metabolic Signaling After Cessation of 5-Fluorouracil Treatment

(PQ 12) 停止 5-氟尿嘧啶治疗后身体功能和骨骼肌代谢信号的调节

基本信息

批准号：
9927604
负责人：
James A Carson
金额：
$ 15.44万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-08 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927604
关键词：
Acute Adult Affect Aftercare Aging Body Weight decreased Cachexia Cancer Patient Cancer Survivor Cessation of life Colon Carcinoma Data Development Diagnosis Disease Dose Effectiveness Endocrine Estradiol Exercise Exercise Test Fatigue Female Fluorouracil Functional disorder Future Goals Gonadal Steroid Hormones Guidelines Health Hypogonadism Inflammation Interleukin-6 Investigation Knowledge Leucovorin Malignant Neoplasms Metabolic Metabolic dysfunction Methotrexate Moderate Exercise Molecular Mus Muscle Muscle Fatigue Muscle Mitochondria Muscle function Occupations Outcome Ovarian Patients Physical Function Physical activity Physiological Play Pre-Clinical Model Prevention Property Quality Control Quality of life Recommendation Regimen Regulation Reporting Role Secondary to Sex Differences Signal Transduction Skeletal Muscle Testing Testosterone Toxic effect Withholding Treatment acute toxicity base cancer cachexia cancer therapy chemotherapy colon cancer patients colorectal cancer treatment exercise training gonad function improved irinotecan male muscle metabolism novel oxaliplatin pre-clinical response sex skeletal muscle metabolism skeletal muscle wasting therapeutic target treadmill

项目摘要

Central objectives for successful cancer treatment include increased survival and improved quality of life. Increased fatigue and decreased physical function remain challenges for most colorectal cancer (CRC) patients after the completion of treatment. CRC patients report functional decrements that cause an inability to perform daily tasks related to shopping, engaging in physical activity, and holding a job. Skeletal muscle loss and metabolic dysfunction play a critical role in these negative outcomes. Historically, the examination of skeletal muscle with cancer has not accounted for the effect of chemotherapy treatment, which has strong potential to alter the health and life quality of cancer survivors. Determining how chemotherapy impacts cancer patients’ long–term health and quality of life after the cessation of treatment is a critically significant question. This proposed study is aligned with Provocative Question 12, “What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?” This question seeks to improve the understanding of chemotherapy complications that extend beyond acute toxicity but can have significant ramifications for patient health and life quality. We seek to understand how sex, gonadal function, and exercise, all of which regulate skeletal muscle function, interact with chemotherapy. Our study will mechanistically examine the effect of exercise dose on skeletal muscle’s response to chemotherapy. Although exercise is widely prescribed, the mechanistic interaction between exercise and chemotherapy is poorly understood. Our study’s focus is based on fundamental discoveries by our group and others who have examined chemotherapy-induced disruptions to skeletal muscle function, and our compelling preliminary data that establishes a novel preclinical paradigm to examine the effects of sex, gonadal function, and exercise dose on skeletal muscle’s response to either Folfox or Folfiri chemotherapy. Our central hypothesis is that either Folfox or Folfiri treatment cause lasting fatigue through the disruption of skeletal muscle mitochondrial quality control in mice, which can be rescued by low dose treadmill exercise and is exacerbated by female gonadal dysfunction. We expect that chemotherapy effects on skeletal muscle are sex dependent, since sex and ovarian function can affect muscle metabolism, inflammation, and IL-6 sensitivity. Specific aim 1 will determine the effect of exercise dose on Folfox or Folfiri regulation of skeletal muscle fatigue and mitochondria quality control in male and female mice. Three treadmill exercise doses that are based on recommendations for cancer survivors will be examined. Specific aim 2 will investigate hypogonadism’s regulation of skeletal muscle fatigue and mitochondria quality control by Folfox or Folfiri treatments and determine if sex hormone administration can modify these outcomes. Our study provides a critical initial examination into the existence of sex differences for chemotherapy-induced muscle dysfunction and should provide the rationale for future investigations into exercise and endocrine-based therapies to treat this dysfunction.

成功的癌症治疗的中心目标包括提高存活率和改善生活质量。疲劳增加和身体机能下降仍然是大多数结直肠癌(CRC)面临的挑战患者完成治疗后。CRC患者报告功能减退，导致不能执行与购物、体力活动和工作相关的日常任务。骨骼肌丢失而代谢功能障碍在这些负面结果中起着关键作用。从历史上看，对骨骼肌癌还没有占化疗治疗的效果，这有很强的有可能改变癌症幸存者的健康和生活质量。确定化疗对癌症的影响患者在停止治疗后的长期健康和生活质量是一个至关重要的问题。这项拟议的研究与具有挑衅性的问题12相一致，“什么是分子和/或细胞癌症治疗引发严重不良后遗症的机制是什么？这问题旨在提高对超出急性毒性的化疗并发症的理解但会对患者的健康和生活质量产生重大影响。我们试图了解性爱是如何，性腺功能和运动，所有这些都调节骨骼肌功能，与化疗相互作用。我们的这项研究将从力学上检验运动剂量对骨骼肌对化疗的反应的影响。尽管运动被广泛地开出处方，运动和化疗之间的机械相互作用是人们对此知之甚少。我们研究的重点是基于我们团队和其他拥有检查了化疗引起的骨骼肌功能紊乱，以及我们令人信服的初步数据这建立了一种新的临床前范式来检验性、性腺功能和锻炼的影响对骨骼肌对Folfox或FOLFIRI化疗的反应的剂量。我们的中心假设是 Folfox或FOLFIRI治疗通过破坏骨骼肌线粒体而导致持久疲劳小鼠的质量控制，小剂量跑步机运动可以挽救这种疾病，雌性加剧了这种情况性腺功能障碍。我们预计化疗对骨骼肌的影响是性别依赖的，因为性别卵巢功能会影响肌肉新陈代谢、炎症和IL-6敏感性。具体目标1将确定运动剂量对Folfox或FolFIRI调节骨骼肌疲劳和线粒体的影响雄性和雌性小鼠的质量控制。基于推荐的三种跑步机运动量癌症幸存者将接受检查。《特定目标2》将研究性腺功能减退对骨骼的调节 Folfox或FolFIRI治疗的肌肉疲劳和线粒体质量控制，并确定性激素管理部门可以修改这些结果。我们的研究提供了一个关键的初步检查的存在化疗所致肌肉功能障碍的性别差异应为今后的研究提供理论基础运动和基于内分泌的疗法治疗这种功能障碍的研究。