TYPE1 DIABETOGENIC GENES CENTROMERIC TO LMP2 IN NOD MICE

NOD 小鼠中 1 型糖尿病基因着丝粒至 LMP2

• 批准号: 6209196
• 负责人: MASAKAZU HATTORI
• 金额: $ 41.03万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6209196
• 关键词: NOD mouse; diabetes mellitus genetics; gene expression; genetic susceptibility; genetically modified animals; histology; insulin dependent diabetes mellitus; major histocompatibility complex

DESCRIPTION: (Adapted from the Investigator's abstract): Type 1 diabetes is a polygenic autoimmune disease in man and the NOD mouse. The genes in the MHC region are the most important in determining susceptibility or resistance to type 1 diabetes. Replacement (homologous recombination) of the NOD MHC class I K region with the R209 MHC class I K region prevented the development of diabetes and insulitis in the intra-MHC recombinant NOD mice. Similarly the replacement of the region of the NOD A, E and D with that of the R209 prevented the development of diabetes and insulitis. The investigators have established six congenic NOD lines with a homozygous segment of r209/r209 in the region of within 6.6 cM centromeric to the Lmp2-hotspot, and two congenic lines with a homozygous segment of r209/r209 in the region of within 3.3 cM from the centromere. Their observation suggests that in addition to the MHC class II A there are three more MHC-linked type 1 diabetogenic genes, two in the region of within 1.1 cM centromeric to the Lmp2 -hotspot, and one in the region of within 3.3 cM from the centromere outside the MHC. One of the first two diabetogenic genes may be the MHC class I K gene itself, otherwise they may be two non-MHC genes in the region. Their proposed studies aim to further restrict the regions including the MHC-linked diabetogenic genes: 1. To see whether the MHC class I K itself is diabetogenic. (1) Establish and screen N3 transgenic NOD mice expressing the MHC class I Kr209(wm7) for the development of diabetes. (2) Histological examination of insulitis and expression of the MHC class I Kr209(wm7) molecules in the N3 transgenic NOD mice (3) Interaction of the transgene Kr209 with the intrinsic r209/r209 chromosomal segment in the congenic line G in the development of diabetes and insulitis 2. To further narrow the region of within 1.0 cM centromeric to K (Iddla), within 1.1 cM centromeric to K(Idd1b) and the region of within 33 cM from the centromere outside the MHC region (Iddlc) to <1.0 cM. (1) Create new recombinant mice by mating the congenic line C with NOD mice for Iddla and Iddlb (2) Create new recombinant mice by mating the congenic line G with NOD mice for Iddlc

描述：（根据调查员的摘要改编）：类型1糖尿病是一个 人和点头小鼠中的多基因自身免疫性疾病。 MHC中的基因 区域在确定易感性或抵抗力方面最重要 1型糖尿病。点头MHC I类替换（同源重组） 具有R209 MHC I类的K区域阻止了 MHC内重组NOD小鼠中的糖尿病和胰岛炎。同样的是 用R209的点数A，E和D的区域替换 糖尿病和胰岛炎的发展。调查人员已经建立了 六个先天点头线，在该地区的R209/R209的纯合细分市场 在6.6 cm的cm centromeric到LMP2-hotspot，两条具有A R209/R209的纯合片段，距离3.3厘米以内 Centromere。他们的观察表明，除了MHC II类A外 另外三个MHC连接1型糖尿病基因，两个在 在1.1 cm的cm centromeric到LMP2 -hotspot，一个在内部的区域中 距MHC外的Centromere 3.3厘米。前两个糖尿病 基因可能是MHC类基因本身，否则它们可能是两个非MHC 该地区的基因。他们提出的研究旨在进一步限制地区 包括MHC连接的糖尿病基因： 1。查看MHC I类本身是否具有糖尿病性。 （1）建立和屏幕N3转基因NOD小鼠表达MHC I类 KR209（WM7）用于糖尿病的发展。 （2）胰岛炎的组织学检查和MHC I类的表达 N3转基因NOD小鼠中的KR209（WM7）分子 （3）转基因KR209与固有的R209/R209染色体的相互作用 糖尿病和胰岛炎的发育中，先天线G中的细分市场 2。进一步缩小1.0 cm centromeric的区域至k（iddla）， 在1.1 cm的cm centromeric到K（IDD1B）和距离33厘米以内的区域内 MHC区域（IDDLC）以外的Centromere至<1.0 cm。 （1）通过与点头C与点头小鼠交配来创建新的重组小鼠 IDDLA和IDDLB （2）通过与点头G与点头小鼠配对，创建新的重组小鼠 IDDLC