Polygenic regulation of murine obesity

小鼠肥胖的多基因调控

• 批准号: 6596830
• 负责人: AAMIR Rafiq ZUBERI
• 金额: $ 30.81万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6596830
• 关键词: dietary lipid; gene environment interaction; genetic mapping; genetic models; genetic polymorphism; genetic regulation; genetic strain; genetic susceptibility; laboratory mouse; microarray technology; nutrition related tag; obesity

DESCRIPTION (provided by applicant): The identification of a novel polygenic obesity gene is the primary goal of this research. Obesity is a disease of excess adipose tissue and the second most preventable cause of death in the United States today. In 2000, an estimated $117 billion was spent treating obesity, primarily on type 2 diabetes, coronary heart disease and hypertension. The 2001 surgeons general report on obesity states that in 1999, 61% of Americans are overweight, along with 13% of children and adolescents. Obesity has doubled since 1980, while overweight among adolescents has tripled. Only 3% of all Americans meet at least four of the five federal recommendations for the intake of grains, fruits, vegetables, diary products, and meats. Less than 33% of Americans exercise for the federally recommended duration and frequency, while 40% of adults are sedentary. Thus, regulation of adiposity through diet and activity, as a public health directive, is inadequate to control this epidemic. Most human obesity is polygenic and genetic variation underlies complex diseases like obesity. We are developing new murine models for polygenic obesity to understand the genetic basis for this disease and to identify the genes responsible. We describe a novel obesity gene positioned within a small 5.2-6.5 cM of mouse Chromosome 2 that regulates adiposity in response to a high fat diet. A congenic mouse strain carrying this gene is significantly reduced in adiposity when fed a high fat diet - most likely due to increased energy expenditure rather than altered food intake- when compared to the background dietary obesity susceptible strain. This observation will be confirmed and extended in subcongenic mouse strains generated to fine-map the location of this gene to an even smaller 0.2-0.5 cM genetic region. Using mouse and human genomic sequence resources, and custom cDNA microarray analysis, we will identify all polymorphic genes in this smaller region that encode variation in protein sequences between the donor and background strains or that differ in expression levels in response to genotype and/or diet composition. The identity of these candidate genes will form the basis behind directed functional assays in downstream studies to identify the underlying novel polygenic obesity gene.

描述（由申请人提供）：新型多基因肥胖基因的鉴定是这项研究的主要目标。肥胖症是脂肪组织过多的疾病，也是当今美国第二大最可预防的死亡原因。 2000年，估计要治疗肥胖症，主要是在2型糖尿病，冠心病和高血压上花费了1,170亿美元。 2001年外科医生关于肥胖症的一般报告指出，1999年，有61％的美国人与13％的儿童和青少年超重。自1980年以来，肥胖已经翻了一番，而青少年的超重却增加了两倍。在所有美国人中，只有3％的美国人在五个联邦建议中至少有四项有关摄入谷物，水果，蔬菜，日记制品和肉类的建议。不到33％的美国人为联邦建议的持续时间和频率进行运动，而40％的成年人久坐不动。因此，作为一项公共卫生指令，通过饮食和活动来调节肥胖，无法控制这种流行病。 大多数人肥胖是多基因和遗传变异是肥胖等复杂疾病的基础。 我们正在为多基因肥胖症开发新的鼠模型，以了解该疾病的遗传基础并确定负责的基因。我们描述了一种新型的肥胖基因，该基因位于小的5.2-6.5 cm小鼠染色体2中，该染色体可调节对高脂肪饮食的肥胖性。与背景饮食肥胖易感性相比，喂养高脂饮食时，富含该基因的先天小鼠菌株的肥胖量显着降低 - 最有可能是由于能量消耗增加而不是食物摄入量所致。该观察结果将被确认并扩展在产生的亚综合小鼠菌株中，该小鼠菌株将该基因的位置定为较小的0.2-0.5 cm遗传区域。使用小鼠和人类的基因组序列资源以及自定义的cDNA微阵列分析，我们将在这个较小的区域中确定所有多态性基因，这些基因编码供体和背景菌株之间蛋白质序列的变化，或者在响应基因型和/或饮食组成的响应中表达水平有所不同。这些候选基因的身份将构成下游研究中定向功能测定的基础，以鉴定潜在的新型多基因肥胖基因。