GENETICS OF MURINE AIRWAY SODIUM ABSORPTION: ROLE IN CF

鼠气道钠吸收的遗传学：在 CF 中的作用

• 批准号: 6638643
• 负责人: Mitchell L Drumm
• 金额: $ 26.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6638643
• 关键词: chloride channels; cystic fibrosis; gene expression; genetic mapping; genetic strain; ion transport; laboratory mouse; respiratory epithelium; sodium

Epithelial ion transport is thought to be an important factor in disorders such as cystic fibrosis (CF), but the regulation of ion movement in vivo is not well understood. In CF, mutations in the chloride channel, CFTR, lead to increased sodium absorption across the respiratory mucosa, a process thought to contribute to the pathophysiology of the CF airway. If the increased absorption does contribute to the disease, it is not clear if it impacts on processes that allow bacterial infection to initiate, or if it aids in allowing the infection to persist, or both. Mechanisms implicating altered salt transport are controversial, but include l) reduced electrolyte levels leading to desiccated mucosa and poor clearance, 2) altering composition of the airway lining fluid in a way that lessens bactericidal activity of antimicrobial peptides, or 3) some other mechanism. Evidence also exists suggesting that the increased sodium absorption may not contribute to the pathophysiology, but is instead a consequence of signaling pathways altered in CF epithelia in response to the CFTR defect. To better understand the in vivo regulation of sodium transport and the role of CFTR in that regulation, this application proposes to map and identify genes contributing to natural variation in nasal transepithelial sodium transport by using inbred mouse lines C57)3L/6J and A/J and their hybrid progeny, recombinant inbred lines, and consomic lines. We have found that the inter-strain variation is quite heritable and is likely due to a small number of genes. To address the role of sodium transport m CF, murine CF alleles will be made congenic on inbred backgrounds associated with different levels of sodium absorption. The influence of sodium absorption on bacterially-mediated lung disease in these mice will be assessed using mice are induced to have a chronic infection by instilling bacteria-laden agar beads into the airway. The ability of the animals to clear the infection, as well as their inflammatory responses, will be monitored.

上皮离子转运被认为是诸如囊性纤维化（CF）等疾病的重要因素，但是体内离子运动的调节尚不清楚。在CF中，CFTR中氯化物通道中的突变导致呼吸道粘膜的钠吸收增加，这一过程被认为有助于CF气道的病理生理。如果增加的吸收确实有助于该疾病，则尚不清楚它是否会影响允许细菌感染启动的过程，或者它是否有助于允许感染持续或两者兼有感染。涉及盐转运改变的机制是有争议的，但包括l）降低的电解质水平，导致粘膜干燥和清除率较差，2）改变气道衬里液体的组成，以减少抗菌肽的细菌活性的方式，或者3）其他机制。证据也存在表明，增加的钠吸收可能不会导致病理生理学，而是响应CFTR缺陷而改变的CF上皮途径的信号传导途径的结果。 To better understand the in vivo regulation of sodium transport and the role of CFTR in that regulation, this application proposes to map and identify genes contributing to natural variation in nasal transepithelial sodium transport by using inbred mouse lines C57)3L/6J and A/J and their hybrid progeny, recombinant inbred lines, and consomic lines.我们发现，应变间变异是相当可遗传的，可能是由于少量基因所致。为了解决钠转运M CF的作用，将在与不同水平的钠吸收水平相关的近交背景上使鼠的CF等位基因保持良好。钠吸收对这些小鼠中细菌介导的肺部疾病的影响将被诱导通过将含细菌的琼脂珠灌输到气道中，从而诱发慢性感染。将监测动物清除感染及其炎症反应的能力。