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）是最广泛研究的高血压遗传模型，就像具有必不可少的高血压的人一样，表现出许多异常的碳水化合物和脂质代谢，代表了心血管疾病的危险因素。然而，尽管进行了广泛的研究，但高血压中代谢风险因素聚集的基础仍然是一个谜。在SHR中介导无序脂肪酸和碳水化合物代谢的介导无序脂肪酸和碳水化合物代谢的定量性状基因座（QTL）的使用，在SHR中介导了一种有力的策略，可以深入了解遗传机制，这些遗传机制是心血管危险危险因素的聚类。因此，该单元的主要目的是对QTL的分子鉴定参与心血管危险因素的聚类 自发性高血压中的疾病。我们已经确定了大鼠染色体10的区域，该区域与SHR中循环水平和胰岛素的循环水平有关。在这个染色体区域内，我们发现SHR在转录因子中具有独特的突变，对葡萄糖和脂肪酸代谢的肝脏控制至关重要。已经发现，靶染色体区域从正常的棕色挪威菌株转移到SHR背景上，可以降低脂肪酸和胰岛素的循环水平。我们假设导致该转录因子的肝过表达的遗传缺陷与CD36中最近发现的SHR缺陷相互作用，以促进无序的脂肪 酸和碳水化合物代谢。因此，我们将使用转基因和先天性菌株的组合直接研究转录因子突变在SHR中危险因素聚类的发病机理中的作用。如果这些突变在该模型中不导致脂质或碳水化合物代谢无序的代谢，则基于先天性菌株中减数分裂映射的替代策略将用于分子鉴定与SHR中新陈代谢干扰有关的QTL。 尽管必须谨慎进行人类和大鼠之间的比较，但预计QTL的分子鉴定在SHR中促进心血管疾病的危险因素的聚类最终将揭示出基本高血压患者的碳水化合物无序的碳水化合物和脂质代谢的发病机理。