Novel Transgenic Rabbit Model for Cardiovascular Disease

新型转基因兔心血管疾病模型

• 批准号: 7404671
• 负责人: Fuliang Du
• 金额: $ 13.27万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7404671
• 关键词: Anatomy; Animal Model; Animals; Biological Models; Biotechnology; Breeding; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular Physiology; Cardiovascular system; Cause of Death; Cells; Cholesterol Ester Transfer Proteins; Clinical Trials; Communities; Disease; Disease model; Drug Delivery Systems; Embryo; Evaluation; Fibroblasts; Gene Targeting; Genes; Goals; Human; Japan; Knock-out; Methods; Modeling; Monkeys; Oryctolagus cuniculus; Pathology; Pharmacologic Substance; Phase; Physiology; Production; Published Comment; Research; Research Personnel; Rodent; Technology; Time; Tobacco; Transgenic Organisms; United States; disease mechanisms study; hepatic lipase; human disease; inhibitor/antagonist; lipid metabolism; mouse model; novel; nuclear transfer; protein function; somatic cell nuclear transfer; therapy development; torcetrapib

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。尽管CVD的研究大大受益于基因靶向的转基因小鼠模型，但这些小啮齿动物并不能准确反映人类心血管生理学。考虑到其在心血管解剖学，生理学和脂质代谢中与人类的许多相似之处，兔子将是CVD研究的出色动物模型。 Evergen的长期目标是建立一个设施，该设施为生物医学和制药界的研究人员提供基因靶向的转基因兔子。在该项目中，Evergen Biotechnologies，Inc。提议通过将专有的体细胞核转移和靶向基因靶向技术结合起来使用方法，以生产第一个靶向基因的转基因兔子作为CVD和其他人类疾病模型，以研究治疗疾病机制和疗法的发展。 在这个项目中，我们建议生产胆固醇酯转移蛋白（CETP）敲除兔子。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了针对人类CETP的药物。辉瑞公司CETP抑制剂最近进行的不利临床试验，Torcetrapib敦促该领域的研究人员提供更好的动物模型系统，以了解靶向CETP的药物的CETP功能和影响。 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基因敲除细胞（CETP）。然后，我们将使用这些细胞进行核转移来产生CETP KO（CETP）胚胎。 在第二阶段，我们将首先关注CETP敲除（CETP）兔子的生产。我们将用肝脂肪酶转基因兔子繁殖CETP KO兔子，以产生人源化的CETP KO兔子。正常兔子的肝脂肪酶活性要比人类低得多。最后，我们将对人性化CETP KO兔子进行病理评估。我们相信，通过拟议的项目，将开发一种可行的方法来生产靶向基因的转基因兔子，我们将首次向全世界的研究人员提供淘汰兔子模型。