Development of a Porcine Model of Atherosclerosis

猪动脉粥样硬化模型的开发

基本信息

批准号：
8301592
负责人：
Christopher Rogers
金额：
$ 60.64万
依托单位：
EXEMPLAR GENETICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8301592
关键词：
Anatomy Animal Model Arterial Fatty Streak Atherosclerosis Balloon Angioplasty Biochemical Biological Models Blood flow Breeding Calcium Cardiovascular Diseases Cardiovascular system Cause of Death Cessation of life Cholesterol Communities Complex Deposition Development Devices Diabetes Mellitus Diagnostic Diet Disease Embryo Engineering Family suidae Female Fibroblasts Gene Targeting Generations Genes Genetic Determinism Genomics Goals Human Hypertension Immunohistochemistry Industry Intervention Lead Life Style Lipids Lipoproteins Low Density Lipoprotein Receptor Low-Density Lipoproteins Measures Medical Device Metabolism Methods Mission Modeling Molecular Mus Mutation Myocardial Infarction Nature Northern Blotting Nuclear Operative Surgical Procedures Organ Patients Pharmaceutical Preparations Phase Physiology Pregnancy Receptor Gene Reporting Research Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Risk Factors Rupture Series Southern Blotting Stents Stroke Testing Therapeutic Thrombosis Time Translating United States Western Blotting Work artery occlusion drug development effective intervention effective therapy fetal human disease hypercholesterolemia mRNA Expression male mouse model novel novel diagnostics novel therapeutics nuclear transfer preclinical study prevent progenitor protein expression receptor somatic cell nuclear transfer tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the primary cause of cardiovascular disease, which is the most common cause of death in the United States. Atherosclerosis is characterized by the accumulation of lipids, cholesterol, calcium deposits, and cellular debris in vessel walls, and results in plaque formation, arterial obstruction, and diminished blood flow to organs. These plaques often rupture, causing myocardial infarction, stroke, or death. The main risk factors include elevated lipid levels, hypertension, and diabetes. Current treatment strategies are directed at changing patient lifestyle/diet and decreasing cholesterol via pharmacological methods. Surgical interventions with medical devices such as stents are used for advanced cases. While these therapeutic approaches have benefited many patients with this disease, they are far from ideal. One reason is that no drug or device is actually developed and tested in a model system that accurately recreates the disease being treated. Thus, there is a significant gap between early phase preclinical studies and human drug trials. The lack of an animal model that accurately replicates all of the manifestations of human atherosclerosis has been a major barrier to the development of effective therapies and interventions for this deadly disease. Several mouse models have been generated with mutations in genes important for lipoprotein metabolism, and while these models have been informative, they fail to develop the complex atherosclerotic lesions that are typical of the human disease. In contrast to mice, the physiology and anatomy of the porcine cardiovascular system closely resembles that of humans. In fact, pigs have long been used as models of cardiovascular disease, and pigs with naturally occurring mutations in their LDL receptor (LDLR) gene, and therefore possessing elevated LDL, have been reported. Although the hypercholesterolemic pig is an attractive model, the mild nature of the mutation, the high variability of the disease, the limited access by other researchers, and the expense prevent its wide use in the research community. Therefore, the ultimate goal of this project is to develop and commercialize a gene- targeted porcine model of atherosclerosis. LDLR fetal fibroblasts that we developed in Phase I will be used as nuclear donors for somatic cell nuclear transfer. Nuclear transfer embryos will be transferred to recipient females for gestation. Resulting piglets will have one targeted LDLR gene. We will characterize the LDLR- targeted pigs at the molecular and biochemical level. We will determine the lipid and lipoprotein profile in LDLR-targeted pigs and perform morphometric analysis to determine the presence and extent of atherosclerosis. Finally, we will establish breeding herds to generate LDLR-/- pigs and to expand and propagate the colony. This project will produce a porcine model of atherosclerosis that will provide academic and industry researchers with an opportunity to better understand the disease and to develop and test new therapeutics and preventative strategies. Thus, this work will accelerate the discovery of novel therapies for this costly and deadly disease.

描述（由申请人提供）：动脉粥样硬化是心血管疾病的主要原因，这是美国最常见的死亡原因。动脉粥样硬化的特征在于血管壁中脂质，胆固醇，钙沉积物和细胞碎屑的积累，并导致斑块形成，动脉阻塞以及流向器官的血液流量减少。这些斑块经常破裂，导致心肌梗塞，中风或死亡。主要危险因素包括脂质水平升高，高血压和糖尿病。当前的治疗策略旨在改变患者的生活方式/饮食，并通过药理学方法降低胆固醇。与医疗设备（例如支架）的手术干预用于晚期病例。尽管这些治疗方法使许多患有这种疾病的患者受益，但它们远非理想。原因之一是，没有在准确地重现所治疗的疾病的模型系统中开发和测试药物或装置。因此，早期临床前研究和人类药物试验之间存在显着差距。缺乏准确复制人动脉粥样硬化的所有表现的动物模型，这是对这种致命疾病有效疗法和干预措施发展的主要障碍。几只小鼠模型是通过对脂蛋白代谢重要的基因突变产生的，尽管这些模型有益，但它们无法发展为人类疾病典型的复杂动脉粥样硬化病变。与小鼠相反，猪心血管系统的生理和解剖学与人类的生理和解剖学相似。实际上，长期以来，猪一直用作心血管疾病的模型，其LDL受体（LDLR）基因中具有天然突变的猪已经报道，因此具有升高的LDL。尽管高胆固醇血症的猪是一个有吸引力的模型，但突变的轻度性质，疾病的高度变异性，其他研究人员的获取有限以及费用阻止了其在研究界的广泛使用。因此，该项目的最终目标是开发和商业化动脉粥样硬化的基因靶向猪模型。我们在第一阶段开发的LDLR胎儿成纤维细胞将用作体细胞核转移的核供体。核转移胚胎将转移到受体女性中进行妊娠。由此产生的小猪将具有一个靶向的LDLR基因。我们将在分子和生化水平上表征LDLR靶向的猪。我们将在靶向LDLR的猪中确定脂质和脂蛋白谱，并进行形态计量分析以确定动脉粥样硬化的存在和程度。最后，我们将建立繁殖牛群来产生LDLR - / - 猪，并扩大和传播殖民地。该项目将产生动脉粥样硬化的猪模型，该模型将为学术和行业研究人员提供更好地理解疾病，开发和测试新的治疗剂和预防策略的机会。因此，这项工作将加速这种昂贵和致命疾病的新疗法的发现。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeted disruption of LDLR causes hypercholesterolemia and atherosclerosis in Yucatan miniature pigs.

DOI：
10.1371/journal.pone.0093457
发表时间：
2014
期刊：
PloS one
影响因子：
3.7
作者：
Davis BT;Wang XJ;Rohret JA;Struzynski JT;Merricks EP;Bellinger DA;Rohret FA;Nichols TC;Rogers CS
通讯作者：
Rogers CS