Primate Model for Pharmaceutical Development

用于药物开发的灵长类动物模型

• 批准号: 6991814
• 负责人: You-Tang Shen
• 金额: $ 12.62万
• 依托单位: VASADE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-05 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6991814
• 关键词: Macaca fascicularis; biological models; cardiovascular disorder chemotherapy; cardiovascular pharmacology; catheterization; congestive heart failure; disease /disorder model; drug design /synthesis /production; functional /structural genomics; heart circulation; heart failure; hemodynamics; implant; model design /development; molecular pathology; myocardial ischemia /hypoxia; pathologic process; pharmacokinetics; proteomics; surgery; ventricular hypertrophy

DESCRIPTION (provided by applicant): With the advances in molecular medicine and genome projects showing many promising opportunities for new strategies of treating human diseases, the number of small pharmaceutical/biotech companies has increased steeply during the past several years. While the research has relied on the full range of available techniques, it has also depended fundamentally on animal models and experiments. However, one significant concern regarding the use of animal models is that results from animal studies are sometimes disparate with clinical outcome, due potentially to major species differences between animals and humans. One of the most important advantages of using nonhuman primate models is their physiological, metabolical, and biochemical similarities to, as well as genetic homology with humans. Currently, there are only few primate research centers in the US, and less than 0.3 % of all lab animals are nonhuman primates. Thus, supporting non-human primate models in research is desperately needed. The first objective of this proposal is to set up a chronically instrumented conscious monkey model, which permits for simultaneous pharmacodynamic and pharmacokinetic studies. To accomplish this, surgical implantation of chronic catheters and transducers to measure cardiac and systemic hemodynamics in non-human primates (Macaca fascicularis) will be performed. Our next objective is to further establish a novel heart failure model in the nonhuman primate, which better servers to elucidate the mechanisms of the heart disease, and to evaluate potential pharmacological interventions. To accomplish this, we propose to use coronary artery ligation in combination with rapid ventricular pacing. One advantage of this combination is to provide the opportunity to study the process from initial myocardial ischemia to compensated left ventricular (LV) hypertrophy, and finally to the end stage of congestive heart failure. Our initial long-term goal is to provide ready access for pharmaceutical companies with a primate model for pharmacodynamic and pharmacokinetic studies, as well as a novel primate model of heart failure, which is optimal for pre-clinical evaluation of novel compounds. A secondary goal is to utilize genomic and proteomic approaches to identify novel genes and proteins that arise during the development of heart failure and patent these molecules for future development. An example of such a novel gene and protein is H11-kinase, which has been characterized by our laboratory and is undergoing patent application by the university and our company.

描述（由申请人提供）：随着分子医学和基因组项目的进展显示出许多治疗人类疾病的新策略的有希望的机会，小型制药/生物技术公司的数量在过去几年中急剧增加。虽然这项研究依赖于所有可用的技术，但它也基本上依赖于动物模型和实验。然而，关于使用动物模型的一个重要问题是，动物研究的结果有时与临床结果不同，这可能是由于动物和人类之间的主要物种差异。使用非人灵长类动物模型的最重要的优势之一是它们与人类的生理、代谢和生化相似性以及遗传同源性。目前，美国只有很少的灵长类动物研究中心，所有实验室动物中只有不到0.3%是非人灵长类动物。因此，迫切需要在研究中支持非人类灵长类动物模型。 本提案的第一个目标是建立一个长期仪器清醒猴模型，允许同时进行药效学和药代动力学研究。为了实现这一点，将在非人灵长类动物（食蟹猴）中进行长期导管和传感器的手术植入，以测量心脏和全身血液动力学。我们的下一个目标是进一步建立一种新的非人灵长类动物心力衰竭模型，更好地服务于阐明心脏病的机制，并评估潜在的药物干预。为此，我们建议使用冠状动脉结扎结合快速心室起搏。这种组合的一个优点是提供了研究从初始心肌缺血到代偿性左心室（LV）肥大，最后到充血性心力衰竭终末期的过程的机会。 我们最初的长期目标是为制药公司提供用于药效学和药代动力学研究的灵长类动物模型，以及用于新型化合物临床前评价的新型心力衰竭灵长类动物模型。第二个目标是利用基因组学和蛋白质组学方法来鉴定心力衰竭发展过程中出现的新基因和蛋白质，并为这些分子申请专利以供未来开发。H11-激酶是这种新基因和蛋白质的一个例子，它已被我们的实验室表征，并正在由大学和我们公司申请专利。