GENES CAUSING SPONTANEOUS OBESITY

导致自发性肥胖的基因

• 批准号: 2906220
• 负责人: CRAIG H WARDEN
• 金额: $ 23.43万
• 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/2906220
• 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调查其机制 小鼠自发性肥胖。 之前的工作已经鉴定出4条染色体 有助于 自发性肥胖 BSB 小鼠的肥胖。 BSB 小鼠是由 (Mus spretus x C57BL/6J) F1 x B6 的回交。 初步数据 可用的同源小鼠品系证实了 chr 上的基因座。 7 影响肥胖。本提案的目的是确定 这些肥胖位点背后的基因。 同类小鼠品系 在 B6 上携带 spretus 染色体区域作为供体 DNA 将创建背景。 作为肥胖的共存 QTL，血浆 小鼠染色体上的胆固醇和肝脂肪酶（HL）活性。发现7个， 已构建的 B6 HL 淘汰赛将用于检验假设 HL 活性的改变决定了这些胆固醇和/肥胖 基因座。 BSB 与 HL KO B6 小鼠回交将产生两种动物 HL 敲除的纯合子和杂合子。 染色体上的 QTL 7；将在这两组中进行比较和对比。 鼠标 Chr. 6,7 和 1 个基因座包含在其 90% 置信区间内， 分别是肥胖、粗壮和解偶联蛋白2基因。 这些候选基因的分子和生化研究将 测试差异是否可以解释观察到的现象 对特质的影响。 如果编码部分存在差异 spretus 和 B6 瘦素，那么生物学结果 将测试差异。 6 号染色体基因座仅与 在 BSB 小鼠中测量的四个脂肪垫之一。 瘦素 mRNA 水平 将确定四个脂肪垫以检查它们与 血浆瘦素和脂肪垫大小。 他们已经发现斯普雷图斯 和 B6 UCP2 有 2 个氨基酸不同，因此 UCP2 的解偶联活性 将对这些菌株进行检查。