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

描述（由申请人提供）：美国估计有1820万人（占总人口的6.3%）患有糖尿病;所有诊断病例的90%至95%为II型糖尿病（NIDDK，2005）。寻找新的和更有效的治疗方法来解决越来越多的美国人患有II型糖尿病和相关疾病，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而受到阻碍。目前市售的所有与代谢综合征和明显的II型糖尿病相关的大鼠模型都具有瘦素受体的遗传缺陷。相反，瘦素和瘦素受体缺陷不是人类人群中肥胖症和糖尿病病因学的常见原因。没有这种缺陷的大鼠模型将更接近人类的情况，因此更适合于研究糖尿病相关疾病和代谢综合征。PreClinomics（PCO）已经开始通过将具有发展糖尿病倾向的选定大鼠模型与具有发展肥胖倾向的模型交叉来开发没有瘦素/瘦素受体缺陷的新大鼠模型。该项目的长期目标是创建一个将被生物技术和制药行业以及研究界接受的大鼠模型，以推进人类II型糖尿病治疗的研究和开发。PCO在该项目的第一阶段达到并超越了其具体目标。第二阶段将重点关注新的糖尿病大鼠模型的持续开发、定义、表征和实用性。 该项目有六个具体目标：1）继续选择性育种，利用遗传监测实现遗传和表型同质性。2)使用饮食操纵来修改肥胖，“代谢综合征”的其他特征和发病年龄和糖尿病发病的同步性。3)测试用于预防和治疗肥胖症和糖尿病的治疗化合物。4)评估出现的时间和水平的已知标志物和终点的肥胖，代谢综合征和糖尿病。5)评估瘦素耐受性。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。这种新的大鼠模型存在强大的商业市场;药物开发商，包括礼来公司，葛兰素史克公司，以及PCO会见的其他公司，已经表达了建立合作安排并最终达成购买协议的强烈兴趣。 项目叙述：目前用于肥胖症和糖尿病研究以及药物开发的市售动物模型具有导致肥胖症的遗传缺陷。这些缺陷在典型的肥胖和糖尿病个体中没有发现，在这些个体中，多基因基因似乎是造成这种状况的原因。该项目的目的是开发和生产一种新的动物模型，该模型具有发展为糖尿病的多基因肥胖症（没有瘦素或瘦素受体缺陷）。这应该是一个非常重要的模型，以开发药物，将控制肥胖和成人发病糖尿病。

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.