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2360万人(占总人口的7%)患有糖尿病；所有确诊病例中90%至95%是2型糖尿病(CDC，2007)。肥胖和代谢综合征是2型糖尿病的主要原因。目前，由于缺乏与导致人类2型糖尿病疾病的肥胖和代谢综合征等疾病非常相似的研究动物模型，寻求更有效的新疗法来应对越来越多的美国人患有2型糖尿病和相关疾病的努力受到阻碍。目前商用的大多数患有肥胖、代谢综合征和2型糖尿病的啮齿动物模型，都存在瘦素受体、瘦素或其他下丘脑肽的遗传缺陷。这些单基因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于在这些人类疾病之间开始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模型来研究肥胖、代谢综合征、2型糖尿病以及由此引起的并发症。2004年，PreOmics(PCO)开始了一项有希望的计划，通过杂交两个具有饮食诱导肥胖和胰岛素抵抗倾向的近交系小鼠模型，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。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：1)继续开发Fatzo小鼠，以实现肥胖和代谢综合征特征的遗传和表型同质性。通过实验证据证实Lepr和Lep基因对外源瘦素的反应性，证实Lepr和Lep基因功能正常。2)鉴定并确认肥胖小鼠体内存在人类代谢综合征/2型糖尿病的已知成分。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的肾素-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用于临床治疗代谢综合征/2型糖尿病的药物的反应性。4)确认模型对饮食控制的反应性，以维持糖尿病前期状态，并加速进展为坦率糖尿病。 公共卫生相关性：由于缺乏相关的动物模型，确定人类肥胖及其相关疾病的新治疗方法的研究受到阻碍。这项工作将描述一种反映人类疾病的新小鼠模型，因此适用于评估潜在的治疗方法。

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. PUBLIC HEALTH RELEVANCE: Research to identify new treatments for human obesity and its related conditions is hindered by the lack of relevant animal models. This effort will describe a new mouse model that reflects the human disease and is therefore applicable for the evaluation of potential treatments.