Novel Transgenic Rabbit Model for Cardiovascular Disease

新型转基因兔心血管疾病模型

• 批准号: 7568584
• 负责人: Fuliang Du
• 金额: $ 59.64万
• 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 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568584
• 关键词: Anatomy; Animal Model; Animal Welfare; Animals; Appendix; Bibliography; Biological Models; Biotechnology; Breeding; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cell Line; Cells; Cholesterol Ester Transfer Proteins; Clinical Trials; Communities; Country; Derivation procedure; Development; Disease model; Drug Delivery Systems; Embryo; Embryo Cloning; Embryonic Development; Environment; Environmental Impact; Equipment; Evaluation; Family suidae; Female; Fibroblasts; Funding; Gene Targeting; Genes; Genetic; Genetic Recombination; Genotype; Goals; Green Fluorescent Proteins; Heart; Homologous Gene; Human; IACUC; In Vitro; Institution; International; Japan; Karyotype; Knock-out; Macaca mulatta; Medical; Medicine; Methods; Michigan; Modeling; Modification; Mus; Names; None or Not Applicable; North America; Numbers; Oryctolagus cuniculus; Other Resources; Pathology; Pharmacologic Substance; Phase; Physiology; Principal Investigator; Production; Published Comment; Research; Research Ethics Committees; Research Personnel; Resource Sharing; Rodent; Staging; Sus scrofa; Technology; Testing; Time; Tobacco; Transgenic Organisms; United States; United States National Institutes of Health; Universities; Vertebrates; Weather; abstracting; blastocyst; cysteine rich protein; disease mechanisms study; drug development; drug discovery; expiration; fetal; hepatic lipase; human CETP protein; human disease; human subject; 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) 是美国最常见的单一死因。尽管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反映人类心血管生理学。考虑到兔子在心血管解剖学、生理学和脂质代谢方面与人类有许多相似之处，因此兔子将成为心血管疾病研究的绝佳动物模型。 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子。在该项目中，Evergen Biotechnologies, Inc.提出采用一种将专有的体细胞核移植和基因靶向技术相结合的方法，生产出第一批基因靶向转基因兔，作为CVD和其他人类疾病模型，用于研究疾病机制和开发治疗方法。 在这个项目中，我们建议生产胆固醇酯转移蛋白（CETP）敲除兔。目前，辉瑞、默克、罗氏、日本烟草等多家公司已开发出针对人类CETP的药物。辉瑞公司的CETP抑制剂Torcetrapib最近的不利临床试验敦促该领域的研究人员提供更好的动物模型系统来了解CETP的功能和针对CETP的药物的作用。 在第一阶段，我们建议靶向兔成纤维细胞中的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来产生 CETP KO (CETP) 胚胎。 在第二阶段，我们将首先关注CETP敲除（CETP）兔的生产。我们将CETP KO兔与肝脂肪酶转基因兔进行繁殖，产生人源化CETP KO兔。正常兔子的肝脂肪酶活性比人类低得多。最后我们将对人源化CETP KO兔进行病理学评价。我们相信，通过所提出的项目，将开发出一种生产基因靶向转基因兔子的可行方法，并且我们将首次向全世界的研究人员提供敲除兔子模型。