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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：
10576873
负责人：
Denis C Guttridge
金额：
$ 50.48万
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/10576873
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 Macrophage 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 bench to bedside cancer cachexia cancer care chemokine chemotherapy combat cytokine effective therapy frailty improved inflammatory milieu insight 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.

摘要