CORE--ENGINEERED MOUSE RESOURCE

核心——工程鼠标资源

• 批准号: 7921920
• 负责人: Bradley K. Yoder
• 金额: $ 31.26万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7921920
• 关键词: Adult; Affect; American; Autosomal Recessive Polycystic Kidney; Biliary; Biological Models; Build-it; Bypass; Cell Line; Cell physiology; Cells; Center Core Grants; Child; Cilia; Classification; Clinical; Clinical Course of Disease; Clinical Trials; Communities; Complement; Cyst; Data; Databases; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Ductal Epithelial Cell; Ductal Epithelium; Engineering; Evaluation; Family; Family Physicians; Fostering; Functional disorder; Gene Activation; Generations; Genes; Genetic; Genetic screening method; Genomics; Genotype; Goals; Health Personnel; Human; In Vitro; Infant; Intention; Kidney; Laboratories; Link; Live Birth; Long-Term Survivors; Measures; Medical; Modeling; Modification; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutation; Natural History; Neurofibromatosis 1; Observational Study; Online Systems; Pathogenesis; Pathology; Patients; Perinatal; Phenotype; Physicians; Plague; Play; Polycystic Kidney Diseases; Reagent; Research Personnel; Resources; Role; Series; Siblings; Structure; Testing; Therapeutic; Transgenic Organisms; Translational Research; Transplantation; cohort; cpk mouse; family management; gene function; genetic resource; in vivo; inclusion criteria; insight; instrument; interest; knockout gene; meetings; mortality; mouse model; mutant; neonate; programs; recombinase; tool

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疾病发病机理提供了重要的见解，是测试潜在治疗方法的重要资源，在多囊性肾脏疾病的情况下，他们对发现囊肿可能源于肾纤毛功能障碍的发现做出了重大贡献。但是，对于许多研究人员而言，使用小鼠模型进行研究具有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的主要局限性，或者很难获得其研究所需的现有突变体。因此，工程小鼠核心（核心B）的主要目标之一是促进小鼠作为研究PKD相关病理的模型系统的使用和可用性。我们将通过为RPKDCC调查人员提供独特的机会来产生型肌次或等位基因的突变，并建立表达可诱导型CRE形式的转基因线的独特机会或一系列等位基因突变。 PKD研究人员的特定导管上皮中的重组酶。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的分析。为了证明我们方法的可行性，核心将重点放在识别小鼠PKHD1中的多个突变上。这些数据将很好地补充与临床和遗传资源核心中人类ARPKD患者正在进行的研究。诱导的CRE重组酶系将允许中断或激活 在“正常”成年小鼠的背景下，RPKDCC研究者感兴趣的特定细胞中的基因。这种重要的修饰将使突变小鼠绕过致死性和严重的发育异常，这些异常困扰了许多基因敲除或囊肿中产生的早期条件突变。使用这些试剂，研究人员现在可以在成人成熟的导管上皮的背景下分析体内基因功能。此外，该核心产生的小鼠资源将用于通过细胞生理核心分离构成或诱导的突变细胞系，以进行随后的体外研究。总体而言，核心的目的是提供独特的资源，以帮助克服RPKDCC调查人员的障碍，以便他们可以利用鼠标进行体内研究或从 它们了解囊肿的功能在导管上皮细胞生理学中。