Genetics of risk factor clustering in hypertension

高血压危险因素聚类的遗传学

• 批准号: 6735483
• 负责人: THEODORE W KURTZ
• 金额: $ 30.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6735483
• 关键词: carbohydrate metabolism; cardiovascular disorder risk; fatty acid metabolism; genetic mapping; genetic models; genetic strain; genetic susceptibility; hypertension; laboratory rat; liver metabolism; quantitative trait loci; spontaneous hypertensive rat; transcription factor

The spontaneously hypertensive rat (SHR) is the most widely studied genetic model of hypertension and like humans with essential hypertension, exhibits a number of abnormalities in carbohydrate and lipid metabolism that represent risk factors for cardiovascular disease. However, despite extensive research, the basis for the clustering of metabolic risk factors in hypertension remains a mystery. The use of Icongenic and transgenic strains to isolate quantitative trait loci (QTL) that mediate disordered fatty acid and carbohydrate metabolism in the SHR represents a powerful strategy for gaining insight into genetic mechanisms that underlie the clustering of cardiovascular risk factors. Accordingly, the primary objective of this unit is the molecular identification of QTL involved in the clustering of risk factors for cardiovascular disease in spontaneous hypertension. We have identified a region of rat chromosome 10 that is linked to the regulation of circulating levels of fatty acids and insulin in the SHR. Within this chromosome region, we have found that the SHR harbors unique mutations in a transcription factor critically important in the hepatic control of glucose and fatty acid metabolism. Transfer of the target chromosome region from the normotensive Brown Norway strain onto the SHR background has been found to decrease circulating levels of fatty acids and insulin. We hypothesize that a genetic defect causing hepatic overexpression of this transcription factor interacts with a recently identified SHR defect in Cd36 to promote disordered fatty acid and carbohydrate metabolism. Therefore, we will use a combination of transgenic and congenic strains to directly investigate the role of the transcription factor mutations in the pathogenesis of risk factor clustering in the SHR. In the event that these mutations do not contribute to disordered lipid or carbohydrate metabolism in this model, an alternative strategy based on meiotic mapping in congenic strains will be used for molecular identification of QTL linked to the metabolic disturbances in SHR. Although comparisons between humans and rats must be made with caution, it is anticipated that the molecular identification of QTL that promote the clustering of risk factors for cardiovascular disease in the SHR will ultimately shed light on the pathogenesis of disordered carbohydrate and lipid metabolism in patients with essential hypertension.

自发性高血压大鼠（SHR）是研究最广泛的高血压遗传模型，并且与患有原发性高血压的人类一样，表现出许多代表心血管疾病危险因素的碳水化合物和脂质代谢异常。然而，尽管进行了广泛的研究，高血压代谢危险因素聚集的基础仍然是一个谜。使用Icongenic和转基因株分离数量性状基因座（QTL），介导的脂肪酸和碳水化合物代谢紊乱的SHR代表了一个强大的战略，深入了解遗传机制，基础上的心血管危险因素的集群。因此，本单元的主要目标是对心血管疾病危险因素聚类中涉及的QTL进行分子鉴定。 自发性高血压病。我们已经确定了大鼠10号染色体的一个区域，该区域与SHR中脂肪酸和胰岛素循环水平的调节有关。在这一染色体区域内，我们发现SHR在一个转录因子中存在独特的突变，该转录因子在肝脏控制葡萄糖和脂肪酸代谢中至关重要。已发现将靶染色体区域从血压正常的Brown Norway品系转移到SHR背景上可降低脂肪酸和胰岛素的循环水平。我们推测，一种遗传缺陷导致肝脏中这种转录因子的过度表达，这种遗传缺陷与最近发现的SHR Cd36缺陷相互作用，促进了肝脏中的脂肪代谢紊乱。 酸和碳水化合物代谢。因此，我们将使用转基因和同源株的组合，直接调查的作用，转录因子突变的发病机制中的危险因素聚集在SHR。如果这些突变不会导致该模型中脂质或碳水化合物代谢紊乱，则将使用基于同源株减数分裂作图的替代策略来分子鉴定与SHR中代谢紊乱相关的QTL。 虽然人类和大鼠之间的比较必须谨慎进行，预计QTL的分子鉴定，促进聚集的心血管疾病的危险因素在SHR最终揭示的发病机制，糖和脂质代谢紊乱的原发性高血压患者。