PRIMATE MODEL FOR PHARMACEUTICAL DEVELOPMENT - 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.
