GENETIC FACTORS IN MURINE ATHEROSCLEROSIS

小鼠动脉粥样硬化的遗传因素

• 批准号: 2216947
• 负责人: Beverly J Paigen
• 金额: $ 26.71万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-08-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216947
• 关键词: alleles; atherosclerosis; biological models; disease /disorder proneness /risk; gel electrophoresis; gene expression; genetic disorder; genetic mapping; genetic strain; genetically modified animals; genotype; high density lipoproteins; laboratory mouse; low density lipoprotein; molecular cloning; molecular pathology; nucleic acid sequence; phenotype; very low density lipoprotein

The long term goal of this laboratory is to identify genetic differences in atherosclerosis susceptibility among inbred mouse strains, to map these genes, to identify the gene products, and to elucidate their roles in the atherosclerotic process. The specific aims of this proposal; are to characterize and map six traits affecting atherosclerosis susceptibility, each of which has some evidence suggesting that the trait is determined by a single gene. These six variants include two (Ath-1, and Ath-2) that affect high density lipoprotein (HDL), one (Ath-5) that affects very low density lipoprotein (VLDL), and three (Ath-6, Ath-7, Ath-8) that affect susceptibility to atherosclerosis without any lipoprotein difference that cosegregates with susceptibility to atherosclerosis among recombinant inbred strains. Ath-1 has already been mapped to a 3 cM region on Chr 1, and in this proposal will be mapped using an interspecific cross to within 0.2 cM, close enough for positional cloning. Ath 2 is tentatively located on Chr 9, and this position will be tested using a congenic at N5 that has the resistant allele of Ath-2 from strain AXB-5 in C57BL/6. A backcross of this congenic to C57BL/6 will be evaluated for cosegregation of atherosclerosis resistance and strain A-like alleles on Chr 9. If Ath-2 is not located on Chr 9, the congenic will be tested for other A-alleles and each A-like regions tested for cosegregation with atherosclerosis in the backcross. Ath-5 is a difference between strains AKR and DBA/2 in the levels of VLDL. It will be mapped by typing loci in the AKXD RI set so that it is completely typed, by finding tentative locations for the trait in the RI set, and by testing these in the backcross. Ath-6 differs between C57BL/6 and C57BL/Ks and is determined by a single gene with smaller lesion size dominant as shown by the distribution of the trait in 37 F2 progeny. The F2 cross is being expanded by another 60 mice in order to carry out the mapping of Ath-6 by testing for all DBA/2-like regions, which constitute 25% of the C57BL/Ks genome. The BXD RI strain set will also be examined to determine whether lesion formation in that RI set can be explained by segregation of Ath-1 and Ath-6 alleles. Ath-7 is a difference between SWR and SJL. Characterizing and mapping this trait requires typing loci in the SWXJ RI set. Ath-8 is a difference in atherosclerosis susceptibility that differs between strains NZB and SM. Segregation in backcross suggests that Ath-8 is determined by a single gene, and the strain distribution of alleles in the NXSM RI set suggests 3 possible locations for this gene.

该实验室的长期目标是确定 近交小鼠菌株中的动脉粥样硬化敏感性，以绘制这些 基因，识别基因产物，并阐明其在 动脉粥样硬化过程。 该提议的具体目的；是 表征并绘制影响动脉粥样硬化敏感性的六个特征， 每个都有一些证据表明特征是由 一个基因。 这六个变体包括两个（ATH-1和ATH-2） 影响高密度脂蛋白（HDL），一种影响非常低的（ATH-5） 脂蛋白密度（VLDL）和影响影响的三个（ATH-6，ATH-7，ATH-8） 对动脉粥样硬化的敏感性，没有任何脂蛋白差异 重组中的动脉粥样硬化易感性 近交菌株。 ATH-1已经映射到ChR 1的3厘米区域，在此中 建议将使用种间杂交绘制为0.2 cm以内 足够接近位置克隆。 ATH 2暂时位于CHR上 9，该职位将使用具有N5的Encenic进行测试 从C57BL/6中的应变AXB-5的ATH-2等位基因。 一个反向 将评估这种对C57BL/6的含量 CHR 9上的动脉粥样硬化抗性和菌株A样等位基因。如果ATH-2为 不在CHR 9上的同类物将对其他A-Clears进行测试，并且 每个A-like区域都测试了与动脉粥样硬化有关 反向交叉。 ATH-5是VLDL级别的菌株AKR和DBA/2之间的差异。 它将通过在AKXD RI集中键入loci来映射它，以便它 通过在RI中找到特征的暂定位置，完全键入 设置，并通过在反向交叉中进行测试。 ATH-6在C57BL/6之间有所不同 和C57BL/ks，由具有较小病变大小的单个基因确定 如37 F2后代中特征的分布所示，主导性。 这 F2十字架正在由另外60只小鼠扩展 通过测试所有DBA/2样区域的ATH-6映射，该区域构成 C57BL/KS基因组的25％。 BXD RI应变集也将检查到 确定该RI组中的病变形成是否可以通过 Ath-1和Ath-6等位基因的隔离。 ATH-7是SWR之间的区别 和sjl。 表征和映射此特征需要在 SWXJ RI集。 ATH-8是动脉粥样硬化敏感性的差异 NZB和SM菌株之间有所不同。 反向交叉中的隔离表明 Ath-8由单个基因确定，并应应变分布 NXSM RI集中的等位基因提出了该基因的3个可能位置。