Murine models to identify CF lung disease modifiers

鉴定 CF 肺部疾病修饰因子的小鼠模型

• 批准号: 6946347
• 负责人: Mitchell L Drumm
• 金额: $ 66.29万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6946347
• 关键词: Pseudomonas aeruginosa; bactericidal immunity; chloride channels; cystic fibrosis; disease /disorder model; gene interaction; genetic mapping; genetic polymorphism; genetic strain; genetic susceptibility; immunogenetics; interleukin 1; interleukin 6; laboratory mouse; lung disorder; medical complication; phenotype

DESCRIPTION (provided by applicant): Man and mouse are currently the only two species that display cystic tibrosis and both can demonstrate significant variation between affected individuals. It seems clear that at least some of the variation is genetic in nature, prompting the use of genetic strategies and state of the art molecular technology to find the genes involved. The restriction of CF to mouse and man limits the choice of model systems one can use to identify genes that modify cystic fibrosis. Of the two, human is obviously the more relevant model to study, but there are significant limitations to carrying out genetic studies in humans. Therefore, the mouse can be used as an adjunct to human studies, providing the ability to control both genetic and non-genetic factors not possible with humans. The drawback, however,.is that one may potentially sacrifice relevance, as there may be CF-associated characteristics between the two species that pertain little to each other. If a model system, such as the mouse, is used to identify genes relevant to CF, it would have the highest chance of success if the phenotypes studied are also relevant to CF, whether it be at the clinical, cellular or biochemical level. In this application we propose to exploit the benefits of the mouse systems by identifying loci that modify CF or CF-related phenotypes. In a related application, we will determine if the human homologues of those genes influence CF in humans. To achieve the goals of this application, the first specific aim is to map loci causing variation in mice for traits relevant to CF, such as those involved responses to Pseudomonas aeruginosa, and CFdependent growth retardation. Our preliminary findings on ion transport genetics indicate multiple genes are involved in the observed variation. For those traits showing multiple contributing loci, we wish to know the contribution of individual loci and how they interact with each other. Therefore, the second aim is to generate congenic mice for loci identified in Aim 1 and related projects by backcrossing and intercrossing consomic mice. Congenics will be generated on both on CF and non-CF backgrounds. Altering CFTR levels appears to have a significant phenotypic effect in patients, but regulatory mechanisms of CFTR expression are poorly understood. We have found tissue- and strain dependent differences in Cftr expression, allowing the potential identification of Cftr transcriptional regulators. Toward this end, the third aim is to identify transcriptional control elements of the Cftr promoter and corresponding transcription factors. The overall goal is to identify genes that affect, or can be manipulated to affect, disease severity in CF patients. To reach that goal, the genes in question must be isolated and their human counterparts identified for study. For this, the final aim is:to identify genes controlling phenotypes in Aim I and controlling expression in Aim 3, as well as their human homologues.

描述（由申请人提供）： 人类和老鼠是目前仅有的两个显示囊性胫骨病的物种 并且两者都可以证明受影响个体之间的显著变化。 很明显，至少有一部分变异是遗传的， 促进使用遗传策略和最先进的分子 寻找相关基因的技术。CF对小鼠和人的限制 限制了模型系统的选择，可以用来识别基因，修改 囊性纤维化在这两者中，人类显然是更相关的模型， 研究，但进行遗传研究有很大的局限性 在人类身上。因此，小鼠可以作为人类研究的辅助工具， 提供控制遗传和非遗传因素的能力， 可能与人类。然而，缺点是， 牺牲相关性，因为可能存在CF相关特征， 两个互不相干的物种如果一个模型系统，如 小鼠，用于鉴定CF相关基因，它将具有最高的 成功的机会，如果研究的表型也与CF相关， 它可以是在临床、细胞或生物化学水平上。在本申请中，我们 建议通过识别基因座来利用小鼠系统的益处， 改变CF或CF相关表型。在相关应用中，我们将 确定这些基因的人类同源物是否影响人类的CF。到 为了实现本申请的目标，第一个具体目标是绘制基因座 导致小鼠与CF相关的性状发生变异，例如 对铜绿假单胞菌的反应和CF依赖性生长迟缓。我们 离子转运遗传学的初步发现表明， 参与了观察到的变化。对于那些表现出多重 贡献基因座，我们希望知道单个基因座的贡献以及如何 它们相互作用。因此，第二个目标是产生 目标1和相关项目中确定的基因座的同源小鼠， 回交和互交同源小鼠。同源基因将在 在CF和非CF背景下。改变CFTR水平似乎有一个 在患者中具有显著的表型效应，但CFTR的调节机制 表达方式不太清楚。我们发现组织和应变依赖于 Cftr表达的差异，允许Cftr的潜在鉴定 转录调节因子。为此，第三个目标是确定 Cftr启动子的转录控制元件和相应的 转录因子 总体目标是确定影响或可以操纵的基因， 影响，CF患者的疾病严重程度。为了达到这个目标， 问题必须被隔离，并确定其人类对应物以供研究。 为此，最终目的是：鉴定控制Aim I中表型的基因 并控制Aim 3及其人类同源物中的表达。

项目成果

Strain-specific variants of the mouse Cftr promoter region reveal transcriptional regulatory elements.

• DOI: 10.1093/hmg/ddh200
• 发表时间: 2004-09
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: L. Ulatowski;Kirstin L Whitmore;T. Romigh;A. VanderWyden;S. Satinover;M. Drumm