Obese diabetic (type II) mouse 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)。肥胖和代谢综合征是导致II型糖尿病的主要原因。目前，由于缺乏与导致人类II型糖尿病疾病的条件非常相似的肥胖研究动物模型，寻求新的、更有效的治疗方法来应对日益增长的美国II型糖尿病和相关疾病的努力受到阻碍。目前商业上可用的大多数啮齿动物模型与肥胖、代谢综合征和II型糖尿病有关，在瘦素受体、瘦素或其他下丘脑肽方面存在遗传缺陷。这些缺陷并不是导致人类肥胖和糖尿病的常见原因。没有这些缺陷的新的小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小鼠模型，该模型没有瘦素/瘦素受体和其他影响下丘脑功能的遗传缺陷，通过杂交两个近亲交配的小鼠模型，有发生饮食诱导的肥胖和胰岛素抵抗的倾向。该项目的长期目标是创建一种将被生物技术或制药行业以及研究界接受的小鼠模型，以推动人类肥胖症和II型糖尿病疗法的研究和开发。该项目的第一阶段将专注于继续开发、定义和表征这种新的肥胖小鼠模型。该项目有四个具体目标。首先，使用表型和遗传监测，继续建立肥胖、代谢综合征和没有瘦素/瘦素受体缺陷的II型糖尿病小鼠模型(Fatzo)，以实现表型和遗传的同质性。第二，研究饮食控制对表型表达(肥胖和II型糖尿病)的起始性、一致性和同步性的影响。第三，展示典型的抗肥胖/抗糖尿病化合物逆转肥胖和预防糖尿病的效果，以显示该小鼠模型的实用性。第四，检测瘦素对Fatzo和对照品系食物消耗的影响。公共卫生相关性：目前用于肥胖、代谢综合征和糖尿病研究和药物开发的商用动物模型存在导致肥胖的瘦素和瘦素相关基因缺陷。在典型的肥胖和糖尿病患者中没有发现这些缺陷，因为在这些人中，似乎有多种基因导致了这种情况。该项目的目的是开发和生产一种新的肥胖和易患糖尿病的小鼠模型，该模型具有多种致病遗传因素，但不存在瘦素或瘦素受体缺陷。这将是控制肥胖症和成人糖尿病药物开发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). Obesity and metabolic syndrome are the leading causes of type II diabetes. 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 an obese research animal model that closely resembles the conditions that lead to the human type II diabetic condition. Most rodent models currently available commercially, related to obesity, metabolic syndrome and type II diabetes, have genetic defects in leptin-receptors, leptin or in other hypothalamic peptides. These 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 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 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 and development of obesity and type II diabetic therapies in humans. Phase I of the project will focus on the continued development, defining, and characterization of this new obese mouse model. The project has four specific aims. First, continue the development of a mouse model (Fatzo) for obesity, metabolic syndrome, and type II diabetes without leptin/leptin-receptor defects using both phenotypic and genetic monitoring to achieve phenotypic and genetic homogeneity. Second, investigate the effects of diet manipulation on the onset, consistency and synchronicity of the phenotypic expression (obesity and type II diabetes). Third, demonstrate the efficacy of typical anti-obesity/anti-diabetic compounds on the reversal of obesity and prevention of diabetes to show the utility of this mouse model. Fourth, examine the effect of leptin on food consumption in Fatzo and control strains. PUBLIC HEALTH RELEVANCE:: Current commercially available animal models that are used for obesity, metabolic syndrome and diabetes research and drug development have leptin and leptin-related genetic defects that cause obesity. These defects are not found in the typical obese and diabetic individuals where multiple genes seem to be responsible for the condition. The purpose of this project is to develop and produce a new obese and diabetes-prone mouse model which has multiple contributing genetic factors but without a leptin or leptin receptor defect. This will be a very important model for the development of drugs that will control obesity and adult onset diabetes.