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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，体重和肌肉质量的无意损失，直接影响患者的生存和生活质量。对于癌症患者和健康人来说，骨骼肌在维持健康方面的作用涉及肌肉质量和肌肉质量，因为它与代谢能力和底物利用灵活性有关。虽然了解肌肉质量损失是恶病质研究的主要焦点，但肌肉质量的降低可能在恶病质的进展和质量损失中都起作用。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，这足以阻碍癌症恶病质的治疗。炎症细胞因子IL-6和肌肉STAT信号是荷瘤小鼠肌肉萎缩的明显调节因子。通过mTOR的肌肉蛋白合成也在恶病质肌中受到抑制。然而，我们对IL-6调节受抑制的肌肉合成代谢信号与癌症恶病质的理解仍然存在重大差距。这一建议在机制上扩展了我们发表的和初步的数据，研究了IL-6在恶病质进展过程中对肌肉蛋白周转的调节。我们的长期目标是通过了解炎症、代谢和激素信号通路的相互作用来破坏肌肉蛋白合成，从而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IL-6细胞因子家族在ApcMin/+和Lewis肺癌（LLC）植入小鼠恶病质发生和发展过程中如何调节营养、激素和肌肉蛋白周转的机械控制。我们的中心假设是通过mTOR信号抑制肌肉蛋白合成是恶病质诱导的肌肉质量损失的基础。这项研究的基本原理是，识别代谢信号通路和这些过程的炎症调节因子将允许治疗对策，可以阻止或逆转癌症肌肉萎缩的进展。在我们之前的研究和使用ApcMin/+和LLC小鼠恶病质模型的初步数据的指导下，我们计划验证我们的中心假设，并实现本应用的三个具体目标：1)确定在恶病质进展过程中，IL-6对蛋白质合成和mTOR信号的调节对喂养和运动的合成代谢抵抗所必需的；2)确定肌肉氧化代谢的改变是否在恶病质进展过程中调节mTOR信号和蛋白质合成；3)确定在恶病质进展过程中，抑制睾酮和雄激素相关信号是否调节mTOR信号和蛋白质转换。这项研究具有创新意义，因为它将研究慢性系统性炎症调节的机械、代谢和激素信号通路，并控制恶病质肌肉蛋白合成的mtor信号调节。这项研究意义重大，因为其结果将导致体育锻炼和药物干预的发展，从而可以干预癌症肌肉萎缩的进展。