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: 9897336
• 负责人: Denis C Guttridge
• 金额: $ 43.52万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9897336
• 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 Airway 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 Cells; 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; progenitor; 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.

抽象的 恶病质是一种使人衰弱的综合征，由于缺乏 骨骼肌质量。这种综合征发生在大多数癌症中，并导致大约三分之一的癌症 占所有癌症死亡的比例。目前，尚无有效的疗法来对抗这种恶性疾病。对于胰腺 癌症 有效恶病质治疗的潜在益处可能比其他恶病质更大 相关恶性肿瘤，因为这些患者中 90% 的体重平均减轻了病前 14%，并且 恶病质极大地限制了他们耐受手术、化疗或放疗的能力。新疗法可能会 源于对导致肌肉萎缩的机制的深入了解。我们最近的努力 重点关注肌肉微环境中肌纤维外部发生的事件。我们表明，循环 肿瘤因子诱导骨骼肌损伤，导致肌肉祖细胞中 NF-kB 的激活， 与参与的再生计划相关。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的 NF-kB 激活也会促进局部肌肉炎症， 其特征是产生细胞因子和趋化因子。这些信号促进了招聘 巨噬细胞表达 M1 炎症因子和 M2 抗炎因子。该应用程序的目标是 检验肌肉祖细胞中的 NF-kB 调节局部炎症环境的假设 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 NF-kB 如何调节癌症恶病质中的局部肌肉炎症； 2) 阐明表型 以及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 深入了解癌症中肌肉萎缩的机制和治疗目标，同时也将拓宽一个领域 目前尚未得到充分探索的恶病质研究。