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

描述（由申请人提供）：美国估计有2360万人（占人口的7%）患有糖尿病；90%到95%的确诊病例是2型糖尿病（疾病预防控制中心，2007年）。肥胖和代谢综合征是2型糖尿病的主要原因。寻找新的和更有效的治疗方法来解决越来越多的美国2型糖尿病患者及相关疾病，目前由于缺乏一种与导致人类2型糖尿病的肥胖和代谢综合征非常相似的研究动物模型而受到阻碍。目前市面上大多数患有肥胖、代谢综合征和2型糖尿病的啮齿动物模型，在瘦素受体、瘦素或其他下丘脑肽中都存在遗传缺陷。这些单基因缺陷并不是人类肥胖和糖尿病的常见病因。没有这些缺陷的新小鼠模型将更接近于在这些人类条件之间开始被认识到的代谢紊乱的连续体。因此，这项工作需要一个更合适的肥胖、代谢综合征、2型糖尿病及其并发症的模型。2004年，PreClinOmics （PCO）开始了一项有前景的计划，通过杂交两种具有饮食性肥胖和胰岛素抵抗倾向的近交小鼠模型，开发一种没有瘦素/瘦素受体和其他影响下丘脑功能的遗传缺陷的新小鼠模型。该项目的长期目标是创建一种小鼠模型，该模型将被生物技术或制药行业以及研究界所接受，以推进人类肥胖、代谢综合征和2型糖尿病治疗方法的研究和开发。该项目的第二阶段将重点关注这种新型肥胖小鼠模型的持续发展、定义和表征。该项目有四个具体目标：1)继续发展Fatzo小鼠，以实现肥胖和代谢综合征性状的遗传和表型同质性。通过对外源性瘦素反应的实验证据证实LepR和Lep基因功能正常。2)鉴定并确认在Fatzo小鼠中存在人类代谢综合征/ 2型糖尿病的已知成分。要检查的成分包括能量消耗减少、血脂异常、高血压、糖皮质激素调节功能障碍、低度炎症、β细胞功能障碍和激活肾素-血管紧张素-醛固酮系统（RAAS）。3)确认模型在预防和治疗策略上对市面上用于代谢综合征/ 2型糖尿病临床治疗的药物的响应性。4)确认模型对饮食操纵的响应性，以维持糖尿病前期状态，并加速糖尿病的进展。

DESCRIPTION (provided by applicant): An estimated 23.6 million people (7 percent of the population) in the United States have diabetes; 90 to 95 percent of all diagnosed cases are type 2 diabetes (CDC, 2007). Obesity and metabolic syndrome are the leading causes of type 2 diabetes. The search for new and more effective therapies to address the growing number of Americans with type 2 diabetes and related conditions is currently hindered by the lack of a research animal model that closely resembles the conditions such as obesity and metabolic syndrome that lead to the human type 2 diabetic condition. Most rodent models currently available commercially that have obesity, metabolic syndrome and type 2 diabetes, have genetic defects in leptin-receptors, leptin or in other hypothalamic peptides. These mono-genetic defects are not common causes for the etiology of obesity and diabetes in the human population. A new mouse model without these defects would more closely resemble the continuum of metabolic disorders that is beginning to be recognized between these human conditions. Thus, a more appropriate model for obesity, metabolic syndrome, type 2 diabetes and the consequent complications is needed for this work. In 2004, PreClinOmics (PCO) began a promising program to develop a new mouse model without leptin/leptin- receptor and other genetic defects which would affect hypothalamic function, by crossing two inbred mouse models with the propensity to develop diet induced obesity with insulin resistance. The long-term goal of this project is to create a mouse model that will be accepted by the biotech or pharmaceutical industries, and the research community to advance the study of and the development of therapies for obesity, metabolic syndrome and type 2 diabetes in humans. Phase II of the project will focus on the continued development, defining, and characterization of this new obese mouse model. The project has four specific aims: 1) Continue development of the Fatzo mouse to achieve genetic and phenotypic homogeneity of traits for obesity and metabolic syndrome. Confirm normal function of LepR and Lep genes by experimental evidence of responsiveness to exogenous leptin. 2) Identify and confirm the presence of known components of human metabolic syndrome/type 2 diabetes in the Fatzo mouse. Components to be examined include reduced energy expenditure, dyslipidemia, hypertension, dysfunctional glucocorticoid regulation, low grade inflammation, beta cell dysfunction and activated renin-angiotensin-aldosterone-system (RAAS). 3) Confirm the models' responsiveness in prevention and treatment strategies to agents marketed for the clinical treatment of metabolic syndrome/type 2 diabetes. 4) Confirm the model's responsiveness to dietary manipulation to maintain the pre-diabetic state as well as to accelerate the progression to frank diabetes.