Cachexia in ApcMin/+ mice: The role of IL-6

ApcMin/ 小鼠恶病质：IL-6 的作用

基本信息

批准号：
9251557
负责人：
James A Carson
金额：
$ 6.29万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251557
关键词：
5&apos -AMP-activated protein kinase Accounting Adipose tissue Androgen Receptor Androgens Antibodies ApcMin/+ mice Behavior Body Weight decreased Cachexia Cancer Patient Case Study Cell Respiration Cessation of life Chronic Clinical Colon Carcinoma Complex Cytokine Signaling Data Development Disease Environment Exercise FRAP1 gene Family Foundations Goals Health Hormonal Implant Individual Inflammation Inflammation Mediators Inflammatory Interleukin 6 Receptor Interleukin-6 Intervention Janus kinase Lead Lewis Lung Carcinoma Malignant Neoplasms Mechanics Metabolic Modeling Mus Muscle Muscle Proteins Muscular Atrophy Nutrient Pathway interactions Patients Pharmacologic Substance Physical activity Play Prevention Process Protein Biosynthesis Publishing Quality of life Receptor Signaling Regulation Reporting Research Resistance Role STAT protein Severities Signal Pathway Signal Transduction Signaling Protein Skeletal Muscle Staging Stimulus Symptoms Testing Testosterone Therapeutic base cancer cachexia cancer type cytokine expectation feeding flexibility improved innovation muscle form muscle metabolism prevent protein degradation research study skeletal muscle wasting targeted treatment tumor wasting

项目摘要

DESCRIPTION (provided by applicant): Cancer cachexia, the unintentional loss of bodyweight and muscle mass, directly impacts patient survival and quality of life. The role of skeletal muscle in maintaining health, for cancer patients and healthy individuals, involves both the amount of muscle mass and the quality of the muscle, as it relates to metabolic capacity and substrate utilization flexibility. Although understanding muscle mass loss is a major focus of cachexia research, reduced muscle quality likely plays a role in both cachexia progression and mass loss. Understanding how the cancer patient's systemic environment disrupts both muscle metabolism and protein turnover regulation remains a challenge that is substantial enough to have impeded cancer cachexia treatment. Inflammatory cytokine IL-6 and muscle STAT signaling are clear regulators of muscle wasting in tumor-bearing mice. Muscle protein synthesis through mTOR is also suppressed in cachectic muscle. However, significant gaps remain in our understanding of the IL-6 regulation of suppressed muscle anabolic signaling with cancer cachexia. This proposal mechanistically extends our published and preliminary data examining IL-6 regulation of muscle protein turnover during the progression of cachexia. Our long-term goal is to improve cancer patient survival through understanding inflammatory, metabolic and hormonal signaling pathway interactions that disrupt muscle protein synthesis. Our study's overall objective is to mechanistically understand how the IL-6 family of cytokines can regulate nutrient, hormonal, and mechanical control of muscle protein turnover during the initiation and progression of cachexia in ApcMin/+ and Lewis Lung Carcinoma (LLC) implanted mice. Our central hypothesis is that muscle protein synthesis suppression through mTOR signaling is fundamental for cachexia- induced muscle mass loss. The rationale for this proposed research is that the identification of metabolic signaling pathways and the inflammatory regulators of these processes will allow therapeutic countermeasures that can block or reverse the progression of muscle wasting with cancer. Guided by our prior research and preliminary data using ApcMin/+ and LLC mouse cachexia models, we plan to test our central hypothesis and accomplish the objectives of this application with three specific aims: 1) Identify the IL-6 regulation of protein synthesis and mTOR signaling necessary for anabolic resistance to feeding and exercise during the progression of cachexia; 2) Determine if alterations in muscle oxidative metabolism regulate mTOR signaling and protein synthesis during the progression of cachexia; and 3) Determine if suppressed testosterone and androgen-associated signaling regulate mTOR signaling and protein turnover during the progression of cachexia. This research is innovative because it will examine mechanical, metabolic, and hormonal signaling pathways that are regulated by chronic systemic inflammation and control mTOR-signaling regulation of muscle protein synthesis with cachexia. It is significant because the results will lead to developing physical activity and pharmaceutical interventions that can intervene in the progression of muscle wasting with cancer.

描述（由申请人提供）：癌症恶病质，体重和肌肉质量的无意丧失，直接影响患者的生存和生活质量。对于癌症患者和健康个体，骨骼肌在维持健康中的作用涉及肌肉质量和肌肉的质量，因为它与代谢能力和底物利用灵活性有关。尽管了解肌肉质量损失是缓存研究的主要重点，但降低的肌肉质量可能在恶病质进展和质量损失中起作用。了解癌症患者的全身环境如何破坏肌肉代谢和蛋白质周转调节仍然是一个挑战，足以阻碍癌症缓存治疗。炎症性细胞因子IL-6和肌肉统计信号传导是肿瘤小鼠中肌肉浪费的明显调节剂。在缓存肌肉中还抑制了通过MTOR合成的肌肉蛋白质。然而，我们对与癌症恶病质抑制肌肉合成代谢信号的IL-6调节的理解保持了巨大差距。该提案从机械上扩展了我们发布的和初步的数据，研究了Cachexia进展过程中肌肉蛋白更新的IL-6调节。我们的长期目标是通过理解破坏肌肉蛋白质合成的炎症，代谢和激素信号通路相互作用来改善癌症患者的生存。我们的研究的总体目标是机械理解的IL-6细胞因子家族如何调节肌肉蛋白转换的营养，激素和机械控制，在APCMIN/+和Lewis Lung Carcinoma（LLC）植入小鼠的启动和进展过程中，肌肉蛋白更新和进展。我们的中心假设是，通过MTOR信号传导抑制肌肉蛋白质抑制是缓存诱导的肌肉质量损失的基础。这项拟议的研究的理由是，这些过程的代谢信号通路和炎症调节剂的鉴定将允许治疗性对策，以阻止或逆转癌症浪费肌肉的进展。在我们先前使用APCMIN/+和LLC小鼠缓存模型的研究和初步数据的指导下，我们计划测试我们的中心假设，并以三个特定的目的来实现此应用程序的目标：1）确定对蛋白质合成和MTOR信号的调节，对在cachexecia的进展过程中对捕获和运动的持续性抵制必要的蛋白质信号和运动所必需。 2）确定肌肉氧化代谢的改变是否调节卡氏症进展过程中MTOR信号传导和蛋白质合成； 3）确定抑制的睾丸激素和与雄激素相关的信号是否调节了恶病质进展过程中MTOR信号传导和蛋白质更新。这项研究具有创新性，因为它将检查由慢性全身炎症和控制MTOR信号调节肌肉蛋白质合成与卡氏症的调节，这些机械，代谢和激素信号通路受到调节。这很重要，因为结果将导致体育锻炼和药物干预措施可以干预癌症的肌肉浪费。