Inducible Tissue-Specific Transgene Expression in Large Animal Biomedical Models

大型动物生物医学模型中诱导型组织特异性转基因表达

• 批准号: 8507526
• 负责人: CHARLES R LONG
• 金额: $ 41.88万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507526
• 关键词: Address; Animal Model; Animals; Development; Disease; Effectiveness; Family suidae; Fatty Liver; Gene Expression; Gene Targeting; Genes; Genetic Engineering; Goals; Homeostasis; Human; In Vitro; Institutes; Insulin Resistance; Investigation; Lentivirus Vector; Metabolic Diseases; Modeling; Muscle; Non-Rodent Model; Obesity; Principal Investigator; Production; Recombinants; Research; Research Proposals; Rodent Model; Role; Scientist; Stearoyl-CoA Desaturase; System; Techniques; Technology; Time; Tissue-Specific Gene Expression; Tissues; Transgenes; United States National Institutes of Health; comparative; functional genomics; gene function; human disease; in vivo; lipid biosynthesis; lipid metabolism; offspring; research study; technology development; therapy development; transgene expression; zygote

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to develop inducible, tissue-specific expression of transgenes to produce large animal models of human disease. There is a critical need to expand functional genomics to non-rodent models and the limited application of technologies, which have been so successful in rodent models, in large animals requires an alternate approach. The specific objective of this proposal is to develop effective tissue-specific, inducible expression of transgenes in vitro, then utilize recombinant lentiviral vectors to deliver these transgenes into porcine zygotes and evaluate the expression platforms in resulting offspring. The target gene for these experiments will be Stearoyl-CoA desaturase (SCD-1) and will serve as an effective and efficient model for examining local control of gene expression in vivo. Although any number of genes could be utilized, SCD-1 has been documented to have an important role in lipid biosynthesis and its tissue specific expression is important in maintaining homeostasis. Therefore, the resulting animals will not only demonstrate the effectiveness of the technology platform, but also serve as a useful model of failed lipid metabolism in a tissue-specific manner. Development of this technology, and utilization of this gene target is central to investigation of diseases such as obesity, insulin resistance and associated metabolic disorders, as well as, muscle and hepatic steatosis. Most importantly, successful completion of this project will result in technological advancements useful to produce a wide variety of biomedical models in numerous large animal species, potentially targeting a huge range of genes, thus benefiting many of the NIH Institutes and Centers.

描述（由申请人提供）：该研究建议的总体目标是开发转基因的诱导性，组织特异性表达，以产生大型的人类疾病动物模型。在大型动物中，在啮齿动物模型中非常成功的技术的应用有限的技术需要将功能基因组学扩展到非变形模型，并且技术的应用有限。该提案的具体目标是在体外开发有效的组织特异性，可诱导的诱导性表达，然后利用重组慢病毒载体将这些转基因传递到猪zygot中，并评估导致后代的表达平台。这些实验的靶基因将是stearoyl-COA去饱和酶（SCD-1），并将作为研究体内基因表达局部控制的有效和有效模型。尽管可以利用任何数量的基因，但已记录了SCD-1在脂质生物合成中起重要作用，其组织特异性表达对于维持稳态很重要。因此，所产生的动物不仅将展示技术平台的有效性，而且还可以作为组织特异性方式的脂质代谢失败的有用模型。这项技术的开发以及该基因靶标的利用对于研究肥胖，胰岛素抵抗和相关代谢性疾病等疾病以及肌肉和肝脂肪变性至关重要。最重要的是，该项目的成功完成将导致技术进步有助于在许多大型动物物种中产生各种生物医学模型，从而有可能针对大量基因，从而使许多NIH研究所和中心受益。