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: 6781019
• 负责人: JULIE E HOOVER-FONG
• 金额: $ 13.72万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781019
• 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（由申请人提供）：CF 患者的 CF 跨膜调节 (CFTR) 基因的两个拷贝均发生突变。 CF 患者血液中脂肪酸 (FA) 的含量也存在可测量的异常。 体内的一些FA可以转化为参与炎症的物质，并且CF患者的炎症生物标志物也被发现存在异常。 在没有 CF 的健康人身上没有发现这些异常。 在 CF 动物模型中，常见受 CF 影响的器官（例如肺和胰腺）中也描述了类似的 FA 水平异常和炎症迹象。因此，异常脂肪酸也可能在人类 CF 疾病表现中发挥作用。在本研究中，目标1和2的目的是测量血浆、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delta F508纯合性CF患者肺部疾病严重程度之间的关系。只有 delta F508 纯合子患者将被纳入目标 1 和 2 中，以便在寻找 CFTR 基因修饰剂时控制 CFTR 基因型，该基因修饰剂可能在脂肪酸失衡和 CF 肺部疾病之间的关系中发挥作用。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，并与他们的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内部和之间的这种关系（脂肪酸异常和肺部疾病），可以确定由环境和遗传因素引起的疾病表现的相对比例。这些努力将帮助我们更好地了解 CF 发病机制以及脂肪酸异常可能对肺部疾病严重程度的影响。预计这些结果将进行进一步的研究，以：1）确定脂肪酸异常与 CF 肺部疾病恶化的自然过程之间的长期关系，2）潜在地改变 CF 患者的这些脂肪酸异常，以期改善疾病结果并最终提高生存率。