Novel Transgenic Rabbit Model for Cardiovascular Disease

新型转基因兔心血管疾病模型

• 批准号: 7676033
• 负责人: Fuliang Du
• 金额: $ 58.87万
• 依托单位: EVERGEN BIOTECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7676033
• 关键词: Anatomy; Animal Model; Animals; Biological Models; Biotechnology; Breeding; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Line; Cells; Cholesterol Ester Transfer Proteins; Cholesterol Esters; Clinical Trials; Communities; Derivation procedure; Development; Disease model; Drug Delivery Systems; Embryo; Embryo Cloning; Embryonic Development; Evaluation; Family suidae; Female; Fibroblasts; Funding; Gene Targeting; Genes; Genetic; Genetic Recombination; Genotype; Goals; Heart; Homologous Gene; Human; In Vitro; Institution; Japan; Karyotype; Knock-out; Macaca mulatta; Medical Research; Medicine; Methods; Michigan; Modeling; Modification; Mus; Names; North America; Oryctolagus cuniculus; Pathology; Pharmacologic Substance; Phase; Physiology; Principal Investigator; Production; Proteins; Published Comment; Research; Research Personnel; Resource Sharing; Rodent; Staging; Technology; Time; Tobacco; Transgenic Mice; Transgenic Organisms; United States; United States National Institutes of Health; Universities; Weather; blastocyst; disease mechanisms study; drug development; drug discovery; fetal; hepatic lipase; human disease; in vitro testing; inhibitor/antagonist; lipid metabolism; mouse model; novel; nuclear transfer; programs; protein function; research facility; response; somatic cell nuclear transfer; therapy development; tool; torcetrapib; translational medicine

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the single most common cause of death in the United States. Although the study of the CVD has greatly benefited from the use of gene-targeted transgenic mouse models, these small rodents do not accurately reflect human cardiovascular physiology. The Rabbit would be an excellent animal model for CVD research, considering its many similarities to humans in cardiovascular anatomy, physiology, and lipid metabolism. The long term goal of Evergen is to establish a facility that provides researchers in the biomedical and pharmaceutical community with gene targeted transgenic rabbits. In this project, Evergen Biotechnologies, Inc. proposes to use an approach by combining the proprietary somatic cell nuclear transfer and the gene-targeting technologies to produce the first gene-targeted transgenic rabbits as CVD and other human disease models for the study of the disease mechanisms and development of therapies. In this project, we propose to produce Cholesterol Ester Transfer Protein (CETP) knockout rabbits. So far, several companies including Pfizer, Merck, Roche, and Japan Tobacco have developed drugs targeting on human CETP. The recent unfavorable clinical trials of Pfizer's CETP inhibitor, Torcetrapib urged researchers in this field to provide a better animal model system to understand the CETP functions and effects of drugs targeting on CETP. In Phase I, we propose to target CETP gene in rabbit fibroblast cells and produce CETP knockout cells (CETP). We will then use these cells for nuclear transfer to produce CETP KO (CETP) embryos. In Phase II, we will first focus on the production of CETP knockout (CETP) rabbits. We will breed CETP KO rabbits with Hepatic Lipase transgenic rabbits to generate humanized CETP KO rabbits. Hepatic Lipase activity is much lower in normal rabbits than in human. Finally we will perform the pathology evaluation of the humanized CETP KO rabbits. We are confident that through the proposed project, a feasible method to produce gene targeted transgenic rabbits will be developed and we will for the first time provide a knockout rabbit model to the researchers worldwide.

描述（由申请人提供）：心血管疾病（CVD）是美国最常见的死亡原因。虽然心血管疾病的研究极大地受益于基因靶向转基因小鼠模型的使用，但这些小型啮齿动物并不能准确地反映人类心血管生理学。考虑到家兔在心血管解剖学、生理学和脂质代谢方面与人类有许多相似之处，家兔将是CVD研究的极好动物模型。 Evergen的长期目标是建立一个设施，为生物医学和制药界的研究人员提供基因靶向转基因兔。在本项目中，Evergen Biotechnologies，Inc.提出采用专有的体细胞核移植与基因打靶技术相结合的方法，制备第一只基因打靶转基因兔，作为CVD等人类疾病模型，用于疾病机制的研究和治疗方法的开发。 在本项目中，我们提出了生产胆固醇酯转移蛋白（CETP）基因敲除兔。到目前为止，包括辉瑞、默克、罗氏和日本烟草在内的几家公司已经开发出针对人类CETP的药物。近期辉瑞公司CETP抑制剂Torcetrapib临床试验的不利结果促使该领域的研究人员提供更好的动物模型系统，以了解CETP的功能和靶向药物对CETP的影响。 在第一阶段，我们建议在兔成纤维细胞中靶向CETP基因并产生CETP敲除细胞（CETP）。然后，我们将使用这些细胞进行核移植，以产生CETP KO（CETP）胚胎。 在第二阶段，我们将首先专注于生产CETP敲除（CETP）兔。我们将用肝脂肪酶转基因兔饲养CETP KO兔，以产生人源化CETP KO兔。正常家兔肝脂酶活性明显低于人。最后，我们将对人源化CETP KO兔进行病理学评价。我们相信，通过拟议的项目，一个可行的方法来生产基因靶向转基因兔，我们将第一次提供敲除兔模型的研究人员在世界各地。

项目成果

Synergistic effect of trichostatin A and scriptaid on the development of cloned rabbit embryos.

• DOI: 10.1016/j.theriogenology.2013.03.003
• 发表时间: 2013-06
• 期刊: Theriogenology
• 影响因子: 2.8
• 作者: Chen CH;Du F;Xu J;Chang WF;Liu CC;Su HY;Lin TA;Ju JC;Cheng WT;Wu SC;Chen YE;Sung LY
• 通讯作者: Sung LY

Follicular oocytes better support development in rabbit cloning than oviductal oocytes.

卵泡卵母细胞比输卵管卵母细胞更好地支持兔子克隆的发育。

• DOI: 10.1089/cell.2011.0030
• 发表时间: 2011
• 期刊: Cellular reprogramming
• 影响因子: 1.6
• 作者: Sung,Li-Ying;Chen,Chien-Hong;Xu,Jie;Lin,Tzu-An;Su,Hwa-Yun;Chang,Wei-Fang;Liu,Chia-Chia;Sung,Yun-Shao;Cheng,WinstonTK;Zhang,Jifeng;Tian,XCindy;Ju,Jyh-Cherng;Chen,YEugene;Wu,Shinn-Chih;Du,Fuliang
• 通讯作者: Du,Fuliang