NF-kB Regulation of the Muscle Microenvironment in Cancer Cachexia

NF-kB 对癌症恶病质肌肉微环境的调节

• 批准号: 10359196
• 负责人: Denis C Guttridge
• 金额: $ 47.81万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-26 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359196
• 关键词: Adipose tissue; Anabolism; Androgen Therapy; Anti-Inflammatory Agents; Appetite Stimulants; Area; Atrophic; Back; Body Weight; Body Weight decreased; Cachexia; Catabolism; Cells; Cessation of life; Chronic Disease; Chronic Kidney Failure; Chronic Obstructive Pulmonary Disease; Clinic; Data; Disease; Event; Fatigue; Fatty acid glycerol esters; GDF8 gene; Goals; Heart failure; Immune; Inflammation; Inflammatory; Laboratories; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Morbidity - disease rate; Mus; Muscle; Muscle Proteins; Muscle satellite cell; Muscular Atrophy; Myoblasts; NF-kappa B; Natural regeneration; Operative Surgical Procedures; Patients; Phase III Clinical Trials; Phenotype; Prevalence; Process; Production; Proteins; Radiation therapy; Regulation; Research; Rheumatoid Arthritis; Role; Sampling; Sarcolemma; Signal Transduction; Skeletal Muscle; Syndrome; Testing; Therapeutic; Translating; Weight; base; bench to bedside; cancer cachexia; cancer care; chemokine; combat; cytokine; effective therapy; frailty; improved; inflammatory milieu; insight; macrophage; mortality; muscle form; novel therapeutics; pancreatic cancer patients; phase II trial; prevent; primary endpoint; programs; recruit; repaired; response; skeletal muscle wasting; stem cells; therapeutic target; tumor; wasting

ABSTRACT Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately a third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer the potential benefit for effective cachexia therapies may be even greater than for other cachexia associated malignancies, since 90% of these patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting. Our recent efforts have focused on events that occur outside the myofiber in the muscle microenvironment. We showed that circulating tumor factors induce skeletal muscle damage leading to the activation of NF-kB in muscle progenitor cells that associated with an engaged regeneration program. However, regeneration is inhibited leading to muscle atrophy. We now find that NF-kB activation in muscle stem cells also promotes a local muscle inflammation, characterized by the production of cytokines and chemokines. These signals promote the recruitment of macrophages expressing M1 inflammatory and M2 anti-inflammatory makers. The goal of this application is to test the hypothesis that NF-kB in muscle progenitor cells regulates this local inflammatory environment that contributes to muscle atrophy. Towards this goal we seek to perform the following two specific aims: 1) Determine how NF-kB regulates local muscle inflammation in cancer cachexia; and 2) Elucidate the phenotype and relevance of macrophages in cancer-induced muscle wasting. Achieving this goal will not only provide insight into the mechanisms and therapeutic targets of muscle wasting in cancer, but will also broaden an area of cachexia research that is currently underexplored.

摘要 恶病质是一种使人衰弱的综合征，它会导致严重的、非自愿的体重下降，原因是体内的 骨骼肌块。这种综合征发生在大多数癌症中，约占三分之一。 在所有癌症死亡中。目前，还没有有效的治疗方法来对抗这种恶性疾病。对于胰腺来说 癌症恶病质有效治疗的潜在益处可能比其他恶病质疗法更大 相关恶性肿瘤，因为90%的患者平均减去了病前14%的体重，以及 恶病质极大地限制了他们对手术、化疗或放射治疗的耐受性。新的治疗方法可能会 从对导致肌肉萎缩的机制的深入了解演变而来。我们最近的努力已经 重点关注肌肉微环境中肌纤维外发生的事件。我们证明了循环 肿瘤因子诱导骨骼肌损伤导致肌祖细胞中核因子-kB的激活 与参与的再生计划有关。然而，再生受到抑制，导致肌肉 萎缩。我们现在发现，肌肉干细胞中核因子-kB的激活也促进了局部肌肉炎症， 以产生细胞因子和趋化因子为特征的。这些信号促进了招聘 巨噬细胞表达M1炎性和M2抗炎标志物。此应用程序的目标是 验证肌肉前体细胞中的核因子-kB调节局部炎症环境的假设 会导致肌肉萎缩。为了实现这一目标，我们力求实现以下两个具体目标：1) 确定核因子-kB如何调节癌症恶病质的局部肌肉炎症；以及2)阐明表型 巨噬细胞在癌症引起的肌肉萎缩中的相关性。实现这一目标不仅将提供 洞察癌症肌肉萎缩的机制和治疗靶点，但也将拓宽一个领域 关于恶病质的研究，目前还没有得到充分的探索。