Lipid Imbalance in CF: Potential CFTR Dysfunction

CF 中的脂质失衡：潜在的 CFTR 功能障碍

• 批准号: 7075356
• 负责人: JULIE E HOOVER-FONG
• 金额: $ 13.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7075356
• 关键词: arachidonate; blood chemistry; chloride channels; clinical research; cystic fibrosis; dizygotic twins; erythrocytes; family genetics; fatty acid metabolism; fatty acid transport; genotype; human subject; lipid metabolism; monozygotic twins; omega 3 fatty acid; pathologic process; patient oriented research; photon absorptiometry; protein structure function; respiratory circulation disorder; respiratory epithelium; siblings; tissue /cell culture

DESCRIPTION (provided by applicant): Patients with CF have mutations in both copies of their CF transmembrane regulator (CFTR) genes. CF patients also have measurable abnormalities in the amount of fatty acids (FAs) in their blood. Some FAs in the body can be converted to substances that participate in inflammation, and biologic markers of inflammation have also been found to be abnormal in CF patients. None of these abnormalities are found in healthy people without CF. Similar abnormalities in FA levels abd signs of inflammation have been described in CF animal models in organs commonly affected in CF, such as the lung and pancreas. Therefore it is possible that anbormal fatty acids could also play a role in CF disease manifestations in humans. In this study, the purpose of Aims 1&2 is to measure fatty acids in plasma, red blood cells and nasal epithelium (as a representative tissue of lung epithelium) and examine the relationship between these fatty acid levels and the severiyt of pulmonary disease in delta F508 homozygous CF patients. Only delta F508 homozygous patients will be included in Aims 1&2 in order to control for CFTR genotype in the search for genetic modifiers of CFTR that could play a role in the relationship between fatty acid imbalance and CF pulmonary disease. In Aim 3, the same fatty acid levels in twins and other siblings with CF will be measured and compared to their pulmonary disease severity. Because of the inherent genetic similarity of twins and siblings, it is possible to determine the relative proportion of their disease manifestations that are due to environment and genetic factors by contrasting this relationship (fatty acid abnormalities and pulmonary disease) within and between twin and sibling pairs. These efforts will help us better understand CF pathogenesis and the influence that fatty acid abnormalities may have on the severity of pulmonary disease. It is anticipated that these results will head to further studies to 1) define the long-term relationship between fatty acid abnormalities and the natural course of deteriorating of CF pulmonary disease and 2) to potentially alter these fatty acid abnormaltiies in CF patients with the hope of improving disease outcome and ultimately survival.

描述（由申请方提供）：CF患者的CF跨膜调节因子（CFTR）基因的两个拷贝均发生突变。 CF患者血液中脂肪酸（FA）的含量也有可测量的异常。 体内的一些脂肪酸可以转化为参与炎症的物质，并且在CF患者中也发现炎症的生物标志物异常。 这些异常在没有CF的健康人中没有发现。 在CF动物模型中，在CF常见受累器官（如肺和胰腺）中也描述了FA水平的类似异常和炎症体征。因此，人造脂肪酸也可能在人类CF疾病表现中发挥作用。在本研究中，目的1和2是测量血浆、红细胞和鼻上皮（作为肺上皮的代表性组织）中的脂肪酸，并检查这些脂肪酸水平与Δ F508纯合子CF患者的肺部疾病严重程度之间的关系。目的1和2中仅纳入Δ F508纯合子患者，以控制CFTR基因型，以寻找可能在脂肪酸失衡和CF肺病之间的关系中发挥作用的CFTR遗传修饰因子。在目标3中，将测量患有CF的双胞胎和其他兄弟姐妹的相同脂肪酸水平，并将其与肺部疾病严重程度进行比较。由于双胞胎和兄弟姐妹固有的遗传相似性，通过对比双胞胎和兄弟姐妹之间的这种关系（脂肪酸异常和肺部疾病），可以确定由于环境和遗传因素引起的疾病表现的相对比例。这些努力将有助于我们更好地了解CF的发病机制和脂肪酸异常可能对肺部疾病严重程度的影响。预计这些结果将用于进一步的研究，以1）确定脂肪酸异常与CF肺病恶化的自然过程之间的长期关系，2）可能改变CF患者的这些脂肪酸异常，希望改善疾病结局并最终改善生存率。