Impaired intestinal barrier function and airway inflammation in cystic fibrosis

囊性纤维化中肠道屏障功能受损和气道炎症

• 批准号: 7706367
• 负责人: ROBERT C DE LISLE
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706367
• 关键词: A Mouse; Affect; Aftercare; Alkaline Phosphatase; Antibiotics; Blood Circulation; Body mass index; Cause of Death; Cystic Fibrosis; Data; Diagnosis; Disease; Distant; Endotoxins; Failure; Fatty acid glycerol esters; Foundations; Functional disorder; Gene Expression; Genes; Goals; Health; Hereditary Disease; Human; Immune; Immune response; Individual; Infection; Inflammation; Ingestion; Intestines; Investigation; Knockout Mice; Lead; Lipopolysaccharides; Longevity; Lung; Lung Inflammation; Malnutrition; Measures; Modeling; Nutritional status; Oral; Organ; Permeability; Phenotype; Plasma; Protein Dephosphorylation; Quality of life; Research; Research Proposals; Respiratory Failure; Respiratory physiology; Role; Serum; Site; Small Intestines; Solid; Source; Testing; Work; airway inflammation; base; cystic fibrosis mouse; cystic fibrosis patients; disease characteristic; effectiveness measure; enzyme activity; feeding; gastrointestinal system; improved; inflammatory marker; insight; laxative; mortality; novel strategies; novel therapeutic intervention; novel therapeutics; nutrition; prevent

DESCRIPTION (provided by applicant): There are about 30,000 cystic fibrosis (CF) patients in the US and another 1,000 individuals are diagnosed annually. The intestinal tract is one of the major organs affected in CF and despite vigorous therapy, malnutrition is common in this disease. Poor nutrition is a strong predictor of mortality in CF patients, whose proximate cause is airway failure due to excessive destructive lung inflammation. The long term research goal is to understand intestinal dysfunction in CF in order to identify new therapeutic directions that improve quality of life and longevity. The objective of this application is to determine the extent to which impaired intestinal function contributes to the excessive immune response in the CF lung. The central hypothesis of this project is that impaired intestinal innate defenses in CF, including decreased alkaline phosphatase (IAP) activity, compromised gut barrier function, and small intestinal bacterial overgrowth, contribute to the excessive immune activity of the lung, which is characteristic of this disease. IAP is part of the innate defenses and is important to intestinal barrier function. Also, lipopolysaccharide (LPS or endotoxin) is a natural substrate of IAP. After dephosphorylation by IAP, LPS is detoxified. Bacterial overgrowth of the CF small intestine is common, which will increase the amount of endotoxin available to enter the circulation. Thus, it is proposed that due to IAP deficiency, increased gut permeability, and intestinal bacterial overgrowth, more bioactive endotoxin from the gut can enter the circulation and reach distant sites like the airways. Gut-derived circulating endotoxin will exacerbate inflammation in the CF lung when infection occurs. A mouse with a targeted disruption of the gene responsible for CF (Cftr knockout mouse) will be used. The CF mouse has several changes in the small intestine that make it an excellent model for human CF disease. The CF mouse also has significantly elevated airway immune activity. Two Specific Aims are proposed for this project: (1) Determine the extent to which the mucosal barrier function of the intestine is impaired in the CF mouse; and (2) Determine the extent to which treatments that ameliorate the CF intestinal phenotype also improve barrier function and decrease airway immune activity in the CF mouse. RELEVANCE: The fatal genetic disease cystic fibrosis (CF) affects about 30,000 people in the US and 1,000 more are diagnosed annually. Poor functioning of the gastrointestinal system is an important factor in the decline in respiratory function which is the eventual cause of death in CF. Successful completion of the proposed project is expected to lead to new therapeutic approaches to improve intestinal function, quality of life, and longevity of CF patients.

描述（由申请人提供）：美国大约有30,000名囊性纤维化（CF）患者，每年诊断出另外1,000名患者。肠道是受CF影响的主要器官之一，尽管剧烈治疗，但营养不良在该疾病中还是很常见的。营养不良是CF患者死亡率的有力预测指标，由于过度破坏性的肺部炎症，其近端原因是气道失败。长期的研究目标是了解CF中的肠道功能障碍，以确定改善生活质量和寿命的新治疗方向。该应用的目的是确定肠功能受损的程度，导致CF肺中过度免疫反应。该项目的中心假设是CF中的肠道先天防御受损，包括碱性磷酸酶（IAP）活性的降低，肠道屏障功能受损和小肠细菌过度生长，有助于肺的过度免疫活性，这是这种疾病的特征。 IAP是先天防御的一部分，对肠道屏障功能很重要。同样，脂多糖（LPS或内毒素）是IAP的天然底物。通过IAP去磷酸化后，LPS被解毒。 CF小肠的细菌过度生长很常见，这将增加可用于进入循环的内毒素的量。因此，有人提出，由于IAP缺乏，肠道渗透性的增加和肠道细菌过度生长，肠道的更多生物活性内毒素可以进入循环并进入远处的位置。当感染发生时，肠道衍生的循环内毒素会加剧CF肺的炎症。将使用具有靶向CF基因（CFTR基因敲除小鼠）的靶向破坏的小鼠。 CF小鼠在小肠中有几种变化，使其成为人类CF疾病的绝佳模型。 CF小鼠还具有显着升高的气道免疫活性。该项目提出了两个具体的目的：（1）确定CF小鼠中肠损伤的粘膜屏障功能的程度； （2）确定改善CF肠表型的治疗方法的程度也可以改善屏障功能并降低CF小鼠的气道免疫活性。 相关性：致命的遗传疾病囊性纤维化（CF）每年诊断出约30,000人，另外1,000人受到诊断。胃肠道系统功能不佳是呼吸功能下降的重要因素，这是CF死亡的最终原因。预计该项目的成功完成将导致新的治疗方法，以改善CF患者的肠道功能，生活质量和寿命。