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（占人口的6.3%）患有糖尿病；90%至95%的确诊病例为II型糖尿病（NIDDK， 2005年）。寻找新的和更有效的治疗方法来解决越来越多的美国II型糖尿病及相关疾病，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。目前市面上所有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病因。没有这种缺陷的大鼠模型将更接近于人类的情况，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，通过将选择的具有糖尿病倾向的大鼠模型与具有肥胖倾向的模型杂交。该项目的长期目标是创建一个大鼠模型，该模型将被生物技术和制药行业以及研究界所接受，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过了其具体目标。第二阶段将重点关注新型糖尿病大鼠模型的持续发展、定义、表征和应用。

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.