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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：
9432821
负责人：
James A Carson
金额：
$ 10.53万
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：
2008
资助国家：
美国
起止时间：
2008-05-05 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9432821
关键词：
5&apos -AMP-activated protein kinase Adipose tissue Androgen Receptor Androgens 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 Fc Receptor 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 Stimulus Symptoms Testing Testosterone Therapeutic cancer cachexia cancer therapy cancer type cytokine expectation experimental study feeding flexibility improved innovation muscle form muscle metabolism prevent protein degradation public health relevance skeletal muscle wasting targeted treatment tumor tumor progression 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，体重和肌肉质量的意外损失，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的量和肌肉的质量，因为它涉及代谢能力和底物利用灵活性。虽然了解肌肉质量损失是恶病质研究的主要焦点，但肌肉质量下降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，足以阻碍癌症恶病质治疗。炎症细胞因子IL-6和肌肉STAT信号传导是荷瘤小鼠肌肉萎缩的明确调节因子。在恶病质肌肉中，通过mTOR的肌肉蛋白质合成也受到抑制。然而，在我们对癌症恶病质中IL-6对抑制肌肉合成代谢信号传导的调节的理解方面仍然存在重大差距。这一建议从机制上扩展了我们已发表的和初步的研究恶病质进展过程中IL-6调节肌肉蛋白质周转的数据。我们的长期目标是通过了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提高癌症患者的生存率。本研究的总体目标是从机制上了解细胞因子IL-6家族如何在ApcMin/+和刘易斯肺癌（LLC）植入小鼠恶病质的开始和进展期间调节营养、激素和肌肉蛋白质周转的机械控制。我们的中心假设是通过mTOR信号传导的肌肉蛋白质合成抑制是恶病质诱导的肌肉质量损失的基础。这项拟议研究的基本原理是，代谢信号通路和这些过程的炎症调节因子的鉴定将允许治疗对策，可以阻断或逆转肌肉萎缩与癌症的进展。在我们先前的研究和使用ApcMin/+和LLC小鼠恶病质模型的初步数据的指导下，我们计划测试我们的中心假设并实现本申请的目标，其具有三个具体目的：1）鉴定恶病质进展期间蛋白质合成和mTOR信号传导的IL-6调节对于对进食和运动的合成代谢抵抗所必需; 2）确定在恶病质进展期间肌肉氧化代谢的改变是否调节mTOR信号传导和蛋白质合成;和3）确定在恶病质进展期间抑制的睾酮和雄激素相关信号传导是否调节mTOR信号传导和蛋白质周转。这项研究是创新的，因为它将检查由慢性全身性炎症调节的机械，代谢和激素信号通路，并控制恶病质肌肉蛋白质合成的mTOR信号调节。这是重要的，因为结果将导致发展身体活动和药物干预，可以干预癌症肌肉萎缩的进展。