Drosophila as a model to study modifiers of Cystic Fibrosis

果蝇作为研究囊性纤维化修饰因子的模型

基本信息

批准号：
10550126
负责人：
Elizabeth Lane
金额：
$ 7.43万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-03 至 2025-03-02
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10550126
关键词：
Affect Bacteria Biological Assay Candidate Disease Gene Cell Line Cells Chloride Channels Chlorides Clinical Colon Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Dehydration Disease Disease Progression Drosophila genus Environmental Risk Factor Epithelial Cells Epithelium European Genes Genetic Genetic Diseases Genetic Screening Germ-Free Goals Human Intestinal Motility Intestines Ion Channel Longevity Lung Messenger RNA MicroRNAs Modeling Mucins Mucous body substance Mutation Newborn Infant Organ Orthologous Gene Other Genetics Outcome Pancreas Pathology Patients Persons Phenotype Proliferating Regulation Regulator Genes Respiratory System Signal Pathway Sinus Sodium Surface Symptoms Therapeutic Time Toxic effect United States Up-Regulation Water Work absorption autosome clinical phenotype clinically relevant cohort cost cystic fibrosis patients differential expression disease phenotype drug action dysbiosis epithelial Na+ channel fly gastrointestinal epithelium inhibitor insight knock-down loss of function mutation microbiome model organism molecular targeted therapies mutant new therapeutic target overexpression recessive genetic trait reproductive organ sensor therapeutic target transcription factor

项目摘要

Summary/abstract Cystic Fibrosis (CF) is genetic disorder that effects approximately 30,000 people in the United states and more then 70,000 worldwide. CF is caused by mutations in the epithelial chloride channel CF transmembrane conductance regulator (CFTR) gene. In CF, loss-of-function mutations in CFTR, reduces chloride efflux from cells, and elevates the activity of the epithelial sodium channel (ENaC) through a mechanism that is not fully understood. This results in an increase sodium and water reabsorption, which ultimately leads to dehydration of the epithelial surface and reduction in mucus transport in multiple mucin-producing organs, such as the lungs, sinuses, intestine, pancreas, and reproductive organs. CF patients develop clinical symptoms in all these mucus- producing organs. In particular, most CF patients have shortened lifespans because of loss of CFTR in the respiratory tract, but also develop gut phenotypes early in the progression of the disease. These gut phenotypes are less studied than the lung phenotypes of CF but still significantly impact CF patients lives. While CF is caused by many different mutations in CFTR, the differences in CFTR function cannot explain the differences in patient symptoms. This indicates that many of the clinical phenotypes of CF are influenced by genetic modifiers and/or environmental factors. These genetic modifiers and environmental factors could be additional targets to develop treatments for CF that could be used to treat all patients regardless of the mutation they harbor. However, many of the potential genetic modifiers of CF are not well studied and the mechanism by which they modify CF phenotypes is unknown. Our lab has recently identified a Drosophila ortholog of the CFTR gene and established a CF model in the fly gut epithelium. In addition to observing CF phenotypes in the gut epithelium of CFTR mutant flies, we uncovered a micro RNA, mir263a, as a negative regulator of ENaC activity. Interestingly, the expression of mir263a is decreased in CFTR mutant flies, suggesting that that the regulation of ENAC by CFTR is regulated in part by mir263a. Here, I propose to further characterize the pathology of the fly mutant model including examining how bacteria can modulate disease phenotypes in this model. I will then use the fly CF model to gain new insight into ENaC, a known modifier of the CF phenotype. Finally, as the short lifespan, low cost, and genetic tractability of the fly makes it an ideal model organism to perform genetic screens, I propose to identify new potential genetic modifiers of CF. Altogether this work will establish Drosophila as a useful model to study CF and potentially provide new molecular targets for treatment of the disease.

摘要/摘要囊性纤维化 (CF) 是一种遗传性疾病，影响美国及其他地区约 30,000 人然后全世界有 70,000 个。 CF 是由上皮氯离子通道 CF 跨膜突变引起的电导调节器（CFTR）基因。在CF中，CFTR的功能丧失突变减少了氯离子的流出细胞，并通过一种尚未完全实现的机制提高上皮钠通道 (ENaC) 的活性明白了。这导致钠和水的重吸收增加，最终导致脱水上皮表面和多个粘蛋白产生器官（例如肺）中粘液运输的减少，鼻窦、肠、胰腺和生殖器官。 CF 患者在所有这些粘液中出现临床症状产生器官。特别是，大多数 CF 患者由于 CFTR 缺失而缩短了寿命。呼吸道，但也在疾病进展的早期形成肠道表型。这些肠道表型与 CF 肺表型相比，其研究较少，但仍对 CF 患者的生活产生重大影响。当CF发生时由于CFTR有许多不同的突变，CFTR功能的差异不能解释患者的差异症状。这表明 CF 的许多临床表型受到遗传修饰因子和/或环境因素。这些基因修饰剂和环境因素可能是开发的额外目标 CF 的治疗方法可用于治疗所有患者，无论他们携带什么突变。然而，许多 CF 的潜在遗传修饰剂以及它们修饰 CF 的机制尚未得到充分研究表型未知。我们的实验室最近鉴定了果蝇CFTR基因的直系同源物，并建立了CF模型果蝇肠上皮。除了观察 CFTR 突变果蝇肠道上皮的 CF 表型外，我们发现了一种微小 RNA，mir263a，作为 ENaC 活性的负调节因子。有趣的是，表达式 CFTR 突变果蝇中 mir263a 减少，表明 CFTR 对 ENAC 的调节受到调节部分由 mir263a 提供。在这里，我建议进一步描述果蝇突变体模型的病理学特征，包括研究细菌如何在此模型中调节疾病表型。然后我将使用 Fly CF 模型来获得对 ENaC（一种已知的 CF 表型修饰剂）的新见解。最后，由于寿命短、成本低、遗传因素苍蝇的易驯化性使其成为进行遗传筛选的理想模型生物，我建议识别新的 CF的潜在遗传修饰剂。总之，这项工作将把果蝇建立为研究 CF 的有用模型并有可能为治疗该疾病提供新的分子靶点。