Atherosclerosis susceptibility genes

动脉粥样硬化易感基因

• 批准号: 6602446
• 负责人: JAN Leslie BRESLOW
• 金额: $ 26.82万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6602446
• 关键词: apolipoprotein E; atherosclerosis; blood lipoprotein metabolism; gender difference; gene expression; gene targeting; genetic mapping; genetic strain; genetic susceptibility; genetically modified animals; inbreeding; laboratory mouse; low density lipoprotein receptor; pathologic process; tissue /cell culture

Utilizing the apo E and LDL receptor knockout mouse models of atherosclerosis, this project proposes to identify new genes and pathways relevant to atherosclerosis susceptibility by applying the powerful techniques of mouse genetics and the emerging tools of the Genome Project. In addition, the experimental approach will heavily emphasize physiological studies of atherosclerosis related phenotypes both as an aid to gene identification and to better stand the function of apo E knockout, and a resistant strain, FVB/N apo E knockout, has revealed 3 atherosclerosis susceptibility loci not associated with lipoprotein phenotype. The specific aims are: 1) To identify the physiological and genetic basis of the knockout, strains. This will entail studies comparing parental strains for lesion progression, tissue contributions, macrophage metabolism, and gene expression. To identify the gene, secondary congenics will be made and the phenotype reconstructed. Secondary congenic will then be backcrossed and recombinants sought to narrow the genetic intervals. Ultimately, the response gene(s) will be identified through gene expression studies, sequencing, and creating transgenic or knockout mouse models. (2) To perform additional crosses between atherosclerosis susceptible and resistant apo E knockout and LDL receptor knockout mouse strains to reveal new genes that control atherosclerosis susceptibility. The first experiment will attempt to identify genes involved in lesion progression by crossing C57/Bl/6J apo E knockout and FVB/N apo E knockout mice with scoring of lesions in F2 mice on a chow diet at 40 weeks of age for lesion size, acellular lipid core size, collagen and smooth muscle cell content, and calcification. A second C57/Bl/6J apo E knockout mice) and FVB/N apo E knockout mice to identify a gender influenced atherosclerosis susceptibility gene. Finally, to create a FVB/N LDL receptor knockout and cross it with the C57Bl/6J LDL receptor knockout strain to identify genes that influence atherosclerosis susceptibility on the LDL receptor knockout but not the apo E knockout background. This project should identify new genes and pathways involved in atherosclerosis susceptibility.

该项目利用apo E和LDL受体敲除动脉粥样硬化小鼠模型，旨在通过应用强大的小鼠遗传学技术和基因组计划的新兴工具来识别与动脉粥样硬化易感性相关的新基因和途径。此外，该实验方法将重点强调动脉粥样硬化相关表型的生理学研究，既可以帮助基因鉴定，也可以更好地发挥apo E敲除的功能，而抗性菌株FVB/N apo E敲除已揭示了3种动脉粥样硬化易感性与脂蛋白表型无关的位点。具体目标是： 1) 确定敲除菌株的生理和遗传基础。这将需要研究比较亲代菌株的病变进展、组织贡献、巨噬细胞代谢和基因表达。为了鉴定该基因，将进行次生同源并重建表型。然后将次生同源体进行回交，并寻求重组体以缩小遗传间隔。最终，将通过基因表达研究、测序和创建转基因或基因敲除小鼠模型来鉴定反应基因。 (2) 在动脉粥样硬化易感性和抗性apo E敲除小鼠品系与LDL受体敲除小鼠品系之间进行额外的杂交，以揭示控制动脉粥样硬化易感性的新基因。第一个实验将尝试通过将 C57/Bl/6J apo E 敲除小鼠和 FVB/N apo E 敲除小鼠杂交来鉴定与病变进展有关的基因，并对 40 周龄时吃饲料的 F2 小鼠的病变大小进行评分，无细胞脂质核心大小、胶原蛋白和平滑肌细胞含量以及钙化。第二个 C57/Bl/6J apo E 敲除小鼠）和 FVB/N apo E 敲除小鼠，以确定性别影响的动脉粥样硬化易感基因。最后，创建 FVB/N LDL 受体敲除株，并将其与 C57Bl/6J LDL 受体敲除株杂交，以鉴定对 LDL 受体敲除但不影响 apo E 敲除背景影响动脉粥样硬化易感性的基因。该项目应确定与动脉粥样硬化易感性相关的新基因和途径。