Genes Modulating Diet-Induced Diabetes in Mice

描述(申请人提供)：2型糖尿病和肥胖症在我国已经成为流行病，预计在未来25年内将有3亿人患上2型糖尿病。对于这些人中的绝大多数人来说，导致疾病发展的致病基因和生化机制尚不清楚。人类连锁研究有助于2%的单基因导致形式的2型糖尿病，但常见病例处于多基因控制之下，特定的致病基因尚未确定。为了加速识别肥胖和2型糖尿病的易感基因，小鼠系统被证明是有用的。我们利用了A/J和C57BL/6菌株，这两种菌株分别对饮食诱导的肥胖和2型糖尿病具有抵抗力和易感性。我们利用了来自A/J和C57BL/6的独特和新的菌株，称为染色体替代菌株(CSSS)，由约瑟夫·纳多博士(凯斯西大学)开发。在C57BL/6的遗传背景中，每个菌株都有一个来自A/J的染色体。这些菌株允许将特定的性状，如体重和血糖水平，快速分配到特定的染色体。它们还促进了在面对高脂肪和高糖饮食的情况下，最终精细定位和识别控制肥胖和糖尿病的基因所需的同源基因图谱的下一步。我们有三个具体的目标，即(1)鉴定含有控制肥胖和糖尿病的基因的染色体，(2)构建含有调控肥胖和糖尿病的染色体间隔的同源菌株，(3)开发用于精细结构定位的杂交。朝着第一个目标的工作进展顺利，我们已经确定了几条染色体，其中包含调节体重和血糖水平的A/J等位基因。第二个和第三个目标将涉及到培育C57BL/6的信息量较大的CSS和重组自交系，以捕捉活跃的A/J等位基因的较小染色体区域。总体而言，这项提议将推动该领域朝着识别控制肥胖症和2型糖尿病复杂疾病的基因迈进。

DESCRIPTION (provided by applicant): Type 2 diabetes and obesity have become epidemics in our country and it is expected that 300 million people will develop type 2 diabetes within the next 25 years. For the vast majority of these individuals, causative genes and biochemical mechanisms leading to disease development remain unknown. Human linkage studies have been helpful for <2% of single genes causing forms of type 2 diabetes, but common cases are under multigenic control, and specific causative genes have not been identified. To accelerate the identification of genes predisposing to obesity and type 2 diabetes, mouse systems are proving useful. We make use of strains A/J and C57BL/6, which are resistant and susceptible, respectively, to diet-induced obesity and type 2 diabetes. We utilize unique and novel strains derived from A/J and C57BL/6 called chromosome substitution strains (CSSs), developed by Dr. Joseph Nadeau (Case Western Univ.). Each strain has one chromosome derived from A/J amongst the genetic background of C57BL/6. These strains allow rapid assignment of specific traits, such as body weight and plasma glucose levels, to specific chromosomes. They also facilitate the next steps of congenic mapping needed to eventually fine map and identify genes controlling obesity and diabetes in the face of high fat and sugar diets. We have three specific aims, which are to (1) Identify chromosomes harboring genes controlling obesity and diabetes, and (2) Construct congenic strains containing chromosomal intervals regulating obesity and diabetes, and (3) Develop crosses for fine structure mapping. Work toward the first aim is progressing well and we have already identified several chromosomes containing A/J alleles modulating body weight and plasma glucose levels. The second and third aims will involve breeding informative CSSs and recombinant inbred lines to C57BL/6 to capture smaller chromosomal regions of active A/J alleles. Overall, this proposal will move the field forward toward identifying genes controlling the complex disorders of obesity and type 2 diabetes.