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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的病原体是一种使人衰弱的综合征，导致由于耗尽而导致严重的非自愿体重减轻骨骼肌质量。该综合征发生在大多数癌症中，大约有助于三分之一在所有癌症死亡中。目前，尚无有效的疗法来抗击这种恶性疾病。用于胰腺癌症有效的缓存疗法的潜在益处可能比其他恶病质更大相关的恶性肿瘤，因为这些患者中有90％平均会损失其罚款前体重的14％，并且恶病质大大限制了其耐受手术，化学或放射疗法的能力。新疗法可能会从对导致肌肉浪费的机制的增强理解中发展。我们最近的努力专注于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素诱导骨骼肌损害，导致肌肉祖细胞中NF-KB的激活，与订婚的再生计划相关。但是，再生被抑制导致肌肉萎缩。现在，我们发现肌肉干细胞中的NF-KB激活还会促进局部肌肉炎症，以细胞因子和趋化因子的产生为特征。这些信号促进了招聘表达M1炎症和M2抗炎制造商的巨噬细胞。该应用的目的是检验以下假设：肌肉祖细胞中的NF-KB调节这种局部炎症环境有助于肌肉萎缩。为了实现这一目标，我们试图执行以下两个具体目标：1）确定NF-KB如何调节癌症恶病质的局部肌肉炎症； 2）阐明表型巨噬细胞在癌症引起的肌肉浪费中的相关性。实现这一目标不仅会提供深入了解癌症中肌肉浪费的机制和治疗靶标，但也将扩大一个区域当前未充分展现的恶病质研究。