Obese diabetic (type II) rat model without leptin/leptin-receptor defects

描述(由申请人提供)：据估计，美国有1820万人(占总人口的6.3%)患有糖尿病；所有确诊病例中90%至95%是II型糖尿病(NIDDK，2005)。目前，由于缺乏与人类糖尿病状况非常相似的研究动物模型，寻找新的、更有效的治疗方法来应对越来越多的美国人患有II型糖尿病和相关疾病的努力受到了阻碍。目前所有商业上可用的与代谢综合征和显性II型糖尿病相关的大鼠模型都存在瘦素受体的遗传缺陷。相反，瘦素和瘦素受体缺陷并不是人类肥胖和糖尿病的常见原因。没有这种缺陷的大鼠模型将更接近人类的情况，因此更适合于糖尿病相关疾病和代谢综合征的研究。PreClinomics(PCO)已经开始开发一种新的没有瘦素/瘦素受体缺陷的大鼠模型，方法是将有患糖尿病倾向的选定大鼠模型与有肥胖倾向的模型杂交。该项目的长期目标是创建一种将被生物技术和制药行业以及研究界接受的大鼠模型，以推动人类II型糖尿病疗法的研究和开发。PCO在这个项目的第一阶段实现并超过了它的具体目标。第二阶段将集中于新的糖尿病大鼠模型的持续开发、定义、特征和实用。 该项目有六个具体目标：1)继续进行选择性育种，并利用遗传监测实现遗传和表型同质性。2)使用饮食调节来调整肥胖、“代谢综合征”的其他特征以及糖尿病的发病年龄和同步性。3)测试预防和治疗肥胖和糖尿病的治疗化合物。4)评估肥胖、代谢综合征和糖尿病的出现时间以及已知标志物和终点的水平。5)评估瘦素耐量。6)与大学和制药合作伙伴合作，产生兴趣、独立的数据和出版物。这种新的老鼠模型存在一个强大的商业市场；包括礼来公司、葛兰素史克公司和PCO会见的其他药物开发商已经表达了建立合作安排和最终购买协议的强烈兴趣。 项目简介：目前用于肥胖和糖尿病研究和药物开发的商业上可用的动物模型存在导致肥胖的基因缺陷。这些缺陷在典型的肥胖和糖尿病患者中没有发现，因为多基因似乎是导致这种情况的原因。该项目的目的是开发和生产一种新的动物模型，该模型具有多基因肥胖(不存在瘦素或瘦素受体缺陷)，并发展为糖尿病。这应该是开发控制肥胖症和成人糖尿病的药物的一个非常重要的模式。

DESCRIPTION (provided by applicant): An estimated 18.2 million people (6.3 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type II diabetes (NIDDK, 2005). The search for new and more effective therapies to address the growing number of Americans with type II diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the human diabetic condition. All rat models currently available commercially, related to metabolic syndrome and overt type II diabetes, have a genetic defect in leptin-receptor. On the contrary, leptin and leptin-receptor defects are not common causes for the etiology of obesity and diabetes in the human population. A rat model without this defect would more closely resemble the human condition and thus be more appropriate for the study of diabetic-related conditions and metabolic syndrome. PreClinOmics (PCO) has begun to develop a new rat model without leptin/leptin-receptor defects by crossing a selected rat model with the propensity to develop diabetes with a model that has the propensity to develop obesity. The long-term goal of this project is to create a rat model that will be accepted by biotech and pharmaceutical industries, and the research community to advance the study and development of type II diabetic therapies in humans. PCO achieved and exceeded its specific aims in Phase I of this project. Phase II will focus on the continued development, defining, characterization and utility of the new diabetic rat model. This project has six specific aims: 1) Continue selective breeding and utilize genetic monitoring to achieve genetic and phenotypic homogeneity. 2) Use dietary manipulation to modify obesity, other characteristics of "metabolic syndrome" and the age of onset and synchronization of the onset of diabetes. 3) Test therapeutic compounds for the prevention and treatment of obesity and diabetes. 4) Evaluate the time of appearance and levels of known markers and endpoints of obesity, metabolic syndrome and diabetes. 5) Evaluate leptin tolerance. 6) Collaborate with University and pharmaceutical partners to generate interest, independent data and publications. A strong commercial market exists for this new rat model; drug developers including Eli Lilly & Company, Glaxo Smith Kline, and others PCO has met with have already expressed a strong interest in establishing collaborative arrangements and eventually purchase agreements. Project Narrative: Current commercially available animal models that are used for obesity and diabetes research and drug development have genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where polygenetic genes seem to be responsible for the condition. The purpose of this project is to develop and produce a new animal model that has polygenetic obesity (does not have a leptin or leptin receptor defect) which develops into diabetes. This should be a very important model to develop drugs that will control obesity and adult onset diabetes.