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）：本研究计划的总体目标是开发可诱导的、组织特异性表达的转基因，以产生人类疾病的大型动物模型。目前迫切需要将功能基因组学扩展到非啮齿动物模型，并且在啮齿动物模型中取得成功的技术在大型动物中的应用有限，需要另一种方法。本方案的具体目标是在体外建立有效的组织特异性、可诱导的转基因表达，然后利用重组慢病毒载体将这些转基因传递到猪受精卵中，并评估其在后代中的表达平台。这些实验的靶基因将是硬脂酰辅酶a去饱和酶（SCD-1），并将作为一种有效和高效的模型来检查体内基因表达的局部控制。尽管可以利用任意数量的基因，但SCD-1已被证明在脂质生物合成中起重要作用，其组织特异性表达在维持体内平衡中起重要作用。因此，由此产生的动物不仅将证明该技术平台的有效性，而且还可以作为组织特异性脂质代谢失败的有用模型。这项技术的发展和利用这一基因靶点对肥胖症、胰岛素抵抗和相关代谢紊乱以及肌肉和肝脏脂肪变性等疾病的研究至关重要。最重要的是，这个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各样的生物医学模型，潜在地针对大量基因，从而使许多NIH研究所和中心受益。