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成为流行病，预计未来25年内将有3亿人患2型糖尿病。对于这些个体中的绝大多数，导致疾病发展的致病基因和生化机制仍然未知。人类连锁研究有助于发现<2%的单基因导致2型糖尿病，但常见病例是在多基因控制下，具体的致病基因尚未确定。为了加速肥胖和2型糖尿病易感基因的鉴定，小鼠系统被证明是有用的。我们利用菌株A/J和C57 BL/6，它们分别对饮食诱导的肥胖和2型糖尿病具有抗性和易感性。我们利用来自A/J和C57 BL/6的独特和新颖的菌株，称为染色体置换菌株（CSS），由Joseph Nadeau博士（凯斯西安大略大学）开发。每个菌株都有一条来自C57 BL/6遗传背景中的A/J的染色体。这些菌株允许将特定性状（如体重和血糖水平）快速分配给特定染色体。它们还促进了同类基因定位的下一步，最终精细定位和识别在高脂肪和高糖饮食下控制肥胖和糖尿病的基因。我们有三个具体的目标，这是（1）确定染色体携带基因控制肥胖和糖尿病，（2）构建同源株含有染色体间隔调节肥胖和糖尿病，（3）发展杂交精细结构定位。朝着第一个目标的工作进展顺利，我们已经确定了几个染色体含有A/J等位基因调节体重和血糖水平。第二个和第三个目标将涉及培育信息CSS和重组近交系C57 BL/6，以捕获活性A/J等位基因的较小染色体区域。总的来说，这一提议将推动该领域朝着确定控制肥胖和2型糖尿病复杂疾病的基因方向发展。

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.