GENES CAUSING SPONTANEOUS OBESITY

导致自发性肥胖的基因

• 批准号: 6178037
• 负责人: CRAIG H WARDEN
• 金额: $ 24.14万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178037
• 关键词: animal genetic material tag; cholesterol; enzyme activity; genetics; hypercholesterolemia; laboratory mouse; leptin; lipase; lipid metabolism; liver metabolism; nucleic acid sequence; obesity; quantitative trait loci

The long-term goal of this research is to investigate the mechanisms of spontaneous obesity in mice. Previous work has identified 4 chromosomal regions (mouse chr. 6,7,12,and 15) or loci (QTLs) that contribute to obesity in spontaneously obese BSB mice. BSB mice were produced by a backcross of (Mus spretus x C57BL/6J) F1 x B6. Preliminary data on an available congenic mouse strains confirm that the locus on chr. 7 affects adiposity. The objective of this present proposal is to identify the genes underlying these obesity loci. Congenic mouse strains carrying the spretus chromosomal regions as donor DNA on the B6 background will be created. As co-incident QTLs for obesity, plasma cholesterol and hepatic lipase (HL) activity on mouse chr. 7 were found, the already constructed B6 HL knockout will used to test the hypothesis that alterations of HL activity determine these cholesterol and/obesity loci. BSB backcrosses with the HL KO B6 mouse will yield animals both homozygous and heterozygous for the HL knock-out. QTLs at chromosome 7; will be compared and contrasted in these two groups. The mouse chr. 6,7, and 1 loci include within their 90 percent confidence intervals, respectively, the obese, tubby, and uncoupling protein 2-genes. Molecular and biochemical studies of these candidate genes will be performed to test whether differences are likely to explain the observed effect on the trait. If there are differences in the coding portion of the spretus and B6 leptin, then the biological consequence of the differences will be tested. The chromosome 6 locus was linked to just one of the four fat pads measured in BSB mice. Leptin mRNA levels in the four fat pads will be determined to examine their correlations with plasma leptin and fat pad sizes. They have already found that spretus and B6 UCP2 differ for 2 amino acids, so uncoupling activity of UCP2 from these strains will be examined.

本研究的长期目标是研究 小鼠自发性肥胖。 以前的工作已经确定了4个染色体 区域（小鼠染色体6、7、12和15）或基因座（QTL），其有助于 自发性肥胖BSB小鼠的肥胖。 BSB小鼠是由一种 （Mus spretus x C57 BL/6 J）F1 x B6的回交。 初步数据显示， 可获得的同类小鼠品系证实， 影响肥胖。本建议的目的是确定 这些肥胖基因的基因。 同类系小鼠 在B6上携带spretus染色体区域作为供体DNA 背景将被创建。 作为肥胖的同时发生的QTL，血浆 在小鼠第7染色体上发现胆固醇和肝脂酶（HL）活性， 已经构建的B6 HL基因敲除将被用于检验假设 HL活性的改变决定了这些胆固醇和/或肥胖 的位点 BSB与HL KO B6小鼠的回交将产生动物， HL敲除的纯合和杂合。 染色体QTL 7;将在这两组中进行比较和对比。 老鼠CHR。 6、7和1位点包括在它们的90%置信区间内， 分别是肥胖、矮胖和解偶联蛋白2基因。 这些候选基因的分子和生物化学研究将是 测试差异是否可能解释观察到的 对性状的影响。 如果存在编码部分的差异， 和B6瘦素，那么， 差异将得到检验。 6号染色体的基因座与 在BSB小鼠中测量的四个脂肪垫之一。 瘦素mRNA水平 四个脂肪垫将被确定，以检查它们与 血浆瘦素和脂肪垫大小。 他们已经发现斯普雷图斯 和B6 UCP 2有2个氨基酸不同，因此UCP 2的解偶联活性 将对这些菌株进行检测。