GUT BARRIER DYSFUNCTION: THE TRIGGER FOR CACHEXIA IN APCMIN/+ MICE

肠道屏障功能障碍：APCMIN/小鼠恶病质的触发因素

• 批准号: 7959766
• 负责人: James A Carson
• 金额: $ 3.7万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959766
• 关键词: Accounting; Address; Analytical Biochemistry; Animal Model; Bacteria; Biochemistry; Blood; Cachexia; Cancer Patient; Cell Wall; Cell secretion; Cessation of life; Chronic; Clinical; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Endotoxemia; Endotoxins; Epithelial Cells; Extravasation; Functional disorder; Funding; Gastrointestinal tract structure; Grant; Hemorrhage; Immune response; Infiltration; Inflammation; Inflammatory; Institution; Interleukin-6; Intestines; Knock-out; Knowledge; Lead; Lipopolysaccharides; Malignant Neoplasms; Malignant neoplasm of lung; Mesentery; Metabolism; Mitochondria; Modeling; Multiple Organ Failure; Mus; Muscle; Muscle Proteins; Muscularis Mucosa; National Cancer Institute; Outcome; Physiology; Prevention; Protein Biosynthesis; Proteolysis; Rattus; Regulation; Research; Research Personnel; Resources; Role; Sepsis; Shock; Signal Transduction; Source; South Carolina; Submucosa; Testing; Tight Junctions; Tumor Burden; Ubiquitin; United States National Institutes of Health; Universities; Work; anticancer research; cytokine; experience; gastrointestinal; lymph nodes; muscle form; neoplastic cell; new therapeutic target; novel; prevent; protein degradation; skeletal muscle wasting; tumor growth; tumorigenesis; wasting

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer cachexia is a condition of whole body wasting that is more common with gastrointestinal tract and lung cancers; cachexia accounts for 30-50% deaths with colon cancer. Thus, the prevention of cachexia is an important objective for the improvement of clinical outcomes in colon cancer patients. Studies on cellular mechanisms involved in muscle wasting indicate that cachexia is initiated by inflammatory signaling, which then activates ATP-dependent ubiquitin-dependent proteasomal degradation of protein, causing loss of muscle mass. Understanding the regulatory mechanisms that integrate inflammatory signaling and muscle proteolysis is critical for understanding cachexia. The PI currently has a RO1 grant funded through the National Cancer Institute to examine inflammatory cytokine IL-6 regulation of muscle protein synthesis and degradation, and muscle mitochondrial function in cachectic ApcMin/+ mice. The source of chronic low level inflammation in ApcMin/+ mice is not well established, but is thought to be related to the immune response to intestinal and colon tumors, and may also involve direct tumor cell secretion of cytokines. A question not addressed by our current funding is the cause of the systemic inflammation that is thought to initiate the skeletal muscle wasting in ApcMin/+ mice. Gut barrier dysfunction (GBD) is a condition where tight junctions between intestinal epithelial cells no longer form an impermeable barrier against bacterial infiltration into the submucosa and muscularis mucosa of the intestine.8 This can lead to endotoxemia (bacterial cell wall fragments in blood) or sepsis (viable bacteria in blood), leading to multiple organ dysfunction syndrome (MODS).7, 21 GBD has been well documented in hemorrhage shock models, and is associated with, and dependent on, increased circulating IL-6 levels; rats with knock-out of IL-6 do not develop GBD.27 We have recently shown that knockout of IL-6 also inhibits development of cachexia and that IL-6 over-expression induces cachexia in ApcMin/+ mice.5 Our preliminary studies demonstrate that a subset of 30 week old ApcMin/+ mice test positive for circulating endotoxin in the blood, and bacteria in the mesenteric lymph nodes. It is not known if GBD with low-level endotoxemia or sepsis, combined with increased expression of IL-6, is a significant source of inflammation that promotes tumorigenesis, tumor growth, and/or cachexia in ApcMin/+ mice. The overall purpose of the current proposal is to determine if gut barrier dysfunction is the primary cause of cachexia in ApcMin/+ mice. To the best of our knowledge the working hypothesis is completely novel. We hypothesize that cachexia is initiated by increased inflammation that results from endotoxin (bacterial lipopolysaccharide or intact bacteria) leakage across the gastrointestinal barrier in ApcMin/+ mice. Additionally, we hypothesize that elevated circulating IL-6 will be necessary to induce endotoxin leakage across the gastrointestinal barrier in ApcMin/+ and ApcMin/+ x Il-6-/- mice. This proposal merges Dr. John Baynes experience in analytical biochemistry, clinical biochemistry, and metabolism with Dr. Carson's understanding of physiology using whole animal models, including the ApcMin/+ mouse. This proposal also servers as a novel project that can bring Dr. Baynes's research expertise closer to the colorectal cancer research group at the University of South Carolina. Completion of this work will lead to a better understanding of the role of GBD and IL-6 signaling in regulation on cachexia, and identify potential novel therapeutic targets to both treat and prevent the cachectic condition. This proposal will provide essential preliminary data for further study in a multi-year RO1 application. Aim 1. Determine if gut barrier dysfunction increases with tumor burden and cachexia in the ApcMin/+ mouse. Aim 2. Determine if inflammatory cytokine IL-6 induces gut barrier dysfunction, in concert with the development of cachexia, in ApcMin/+ and ApcMin/+ x IL-6 -/- mice.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 癌症恶病质是整个身体浪费的疾病，在胃肠道和肺癌中更常见。恶病质占结肠癌的30-50％死亡。因此，预防卡氏症是改善结肠癌患者临床结果的重要目标。 有关肌肉浪费的细胞机制的研究表明，炎症信号传导引发了恶病质，然后激活蛋白质的蛋白质依赖ATP依赖性泛素依赖性蛋白酶体降解，从而导致肌肉质量丧失。 了解整合炎症信号传导和肌肉蛋白水解的调节机制对于理解恶病质至关重要。 PI目前拥有通过国家癌症研究所资助的RO1赠款，以检查肌肉蛋白合成和降解的炎性细胞因子IL-6调节，以及在缓存的APCMIN/+小鼠中的肌肉线粒体功能。 APCMIN/+小鼠中慢性低水平炎症的来源尚未确定，但被认为与对肠道和结肠肿瘤的免疫反应有关，并且也可能涉及细胞因子的直接肿瘤细胞分泌。我们当前的资金未解决的一个问题是造成系统性炎症的原因，被认为会引发APCMIN/+小鼠中的骨骼肌浪费。 Gut barrier dysfunction (GBD) is a condition where tight junctions between intestinal epithelial cells no longer form an impermeable barrier against bacterial infiltration into the submucosa and muscularis mucosa of the intestine.8 This can lead to endotoxemia (bacterial cell wall fragments in blood) or sepsis (viable bacteria in blood), leading to multiple organ dysfunction syndrome （mods）.7，21 GBD在出血性休克模型中已被充分记录，并且与循环IL-6水平增加相关并取决于并取决于增加的IL-6水平； 27我们最近表明，IL-6的敲除也抑制了恶病质的发育，而IL-6过表达在APCMIN/+小鼠中诱导了红甲氧乙烯。5我们的初步研究表明，30周的Baccmin/+ Mia commitia commia commia compcmin andoxin conteria contecin，cachexia cachexia a cachexia a cachexia cachexia。5我们的初步研究表明，30周的BACETER对循环的呈循环呈循环序列，循环呈循环，这是循环的，这表明，IL-6的敲除也抑制了Cachexia。淋巴结。尚不清楚患有低水平内毒素血症或败血症的GBD是否是IL-6表达增加的GBD，是促进apcmin/+小鼠中肿瘤发生，肿瘤生长和/或恶病质的重要来源。 当前建议的总体目的是确定肠道屏障功能障碍是否是apcmin/+小鼠恶病质的主要原因。据我们所知，工作假设是完全新颖的。我们假设恶病质是由炎症增加的炎症引起的，该炎症是由内毒素（细菌脂多糖或完整细菌）泄漏到胃肠道/+小鼠中胃肠道屏障的泄漏。此外，我们假设升高的循环IL-6对于在APCMIN/+和APCMIN/APCMIN/+ X IL-6 - / - 小鼠中诱导内毒素泄漏是必要的。该提案将约翰·贝恩斯博士的分析生物化学，临床生物化学和代谢方面的经验与卡森博士使用包括APCMIN/+小鼠在内的整个动物模型（包括APCMIN/+小鼠）的生理学理解相结合。该建议还作为一个新型项目，可以使Baynes博士的研究专业知识更接近结直肠癌研究小组 南卡罗来纳大学。这项工作的完成将使人们更好地了解GBD和IL-6信号在调节中的作用，并确定潜在的新型治疗靶标，以治疗和预防缓存状况。该提案将在多年的RO1应用中提供基本的初步数据，以进一步研究。 AIM 1。确定肠道障碍功能障碍是否会随着APCMIN/+小鼠的肿瘤负担和恶病质的增加而增加。 AIM 2。确定炎症性细胞因子IL-6是否诱导肠道屏障功能障碍，与Cachexia的发展，APCMIN/+和APCMIN/+ aPCMIN/+ X IL-6 - / - 鼠标。