CORE--ENGINEERED MOUSE RESOURCE

核心——工程鼠标资源

• 批准号: 7069751
• 负责人: Bradley K. Yoder
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069751
• 关键词: alleles; autosomal recessive trait; biomedical facility; biotechnology; disease /disorder model; epithelium; gene induction /repression; gene mutation; genetic manipulation; genetically modified animals; kidney cell; laboratory mouse; model design /development; polycystic kidney; recombinase

Mouse models of human disorders have provided essential insights into disease pathogenesis, are an important resource to test potential therapeutic approaches, and in the case of polycystic kidney disease, they have made major contributions to the discovery that cysts can arise from dysfunction of renal cilia. However, for many investigators, using mouse models for their studies has major limitations associated with the expense and expertise required to generate and characterize the phenotype of a new mouse mutant or they have difficulty in obtaining an existing mutant necessary for their study. Therefore, one of the major goals of the Engineered Mouse Core (Core B) is to foster the use and availability of the mouse as a model system to study PKD related pathologies. We will accomplish this by providing RPKDCC investigators with a unique opportunity to generate hypomorphic or an allelic series of mutations in genes or regions of genes of interest and by establishing transgenic lines that express inducible forms of Cre recombinase within specific ductal epithelium of interest to PKD researchers. The generation of allelic series of mutations will facilitate structure-function studies and analysis of phenotype-genotype correlations. As a demonstration of the feasibility of our approach, the Core will focus in the initial year on identifying multiple mutations in mouse Pkhd1. These data will nicely complement ongoing studies with human ARPKD patients in the Clinical and Genetic Resource Core. The inducible Cre recombinase lines will permit disruption or activation of genes in specific cells of interest to the RPKDCC investigator in the context of a "normal" adult mouse. This important modification will allow the mutant mice to bypass lethality and the severe developmental abnormalities that have plagued many of the gene knockouts or early conditional mutations generated in the cystogenes. With these reagents, investigators can now analyze gene function in vivo in the context of a mature ductal epithelium of the adult. Furthermore, the mouse resources generated from this Core will be used for the isolation of constitutive or inducible mutant cell lines by the Cell Physiology Core for subsequent in vitro studies. Overall, the intention of the core is to provide unique resources that will help overcome barriers for RPKDCC investigators, so that they can utilize the mouse for in vivo studies or cell lines derived from them to understand the function of cystogenes in ductal epithelial cell physiology.

人类疾病的小鼠模型为了解疾病发病机制提供了重要的见解，是测试潜在治疗方法的重要资源，在多囊肾病的情况下，它们为发现囊肿可能由肾纤毛功能障碍引起的发现做出了重大贡献。然而，对于许多研究人员来说，使用小鼠模型进行研究具有重大局限性，这些局限性与生成和表征新小鼠突变体表型所需的费用和专业知识有关，或者他们难以获得研究所需的现有突变体。因此，工程小鼠核心 (Core B) 的主要目标之一是促进小鼠作为模型系统的使用和可用性，以研究 PKD 相关病理学。我们将通过为 RPKDCC 研究人员提供独特的机会来实现这一目标，以在感兴趣的基因或基因区域中产生亚等位基因或一系列等位基因突变，并建立表达可诱导形式 Cre 的转基因系。 PKD 研究人员感兴趣的特定导管上皮内的重组酶。等位基因突变系列的产生将促进结构功能研究和表型基因型相关性分析。为了证明我们方法的可行性，核心将在第一年重点识别小鼠 Pkhd1 中的多个突变。这些数据将很好地补充临床和遗传资源核心中正在进行的针对人类 ARPKD 患者的研究。诱导型 Cre 重组酶系将允许破坏或激活 在“正常”成年小鼠的背景下，研究 RPKDCC 研究者感兴趣的特定细胞中的基因。这一重要的修饰将使突变小鼠绕过致命性和严重的发育异常，这些异常困扰着许多基因敲除或在囊肿基因中产生的早期条件突变。有了这些试剂，研究人员现在可以在成人成熟导管上皮的背景下分析体内基因功能。此外，从该核心产生的小鼠资源将用于细胞生理学核心分离组成型或诱导型突变细胞系，用于后续体外研究。总体而言，核心的目的是提供独特的资源，帮助 RPKDCC 研究人员克服障碍，以便他们能够利用小鼠进行体内研究或源自 RPKDCC 的细胞系 他们了解囊肿基因在导管上皮细胞生理学中的功能。