New Experimental Models of Hypertension

描述（由申请人提供）：原发性高血压通常与糖尿病和心血管疾病的多种风险因素聚集相关，包括胰岛素抵抗、血脂异常以及血压升高。心脏病和糖尿病的多种风险因素的聚集通常被称为代谢综合征，据报道影响25%的普通人群和多达50%的高血压患者。众所周知，减肥和运动可以有效地改善高血压、糖尿病和代谢综合征，然而，这种生活方式的改变在临床实践中往往难以实现。此外，许多患有高血压或肥胖症的患者不会发展成代谢综合征或糖尿病。因此，希望鉴定使患者易患高血压代谢综合征的遗传机制将最终有助于指导新的预防和治疗方法的开发。自发性高血压大鼠（SHR）是研究最广泛的高血压遗传模型，与患有原发性高血压的人类一样，表现出许多碳水化合物和脂质代谢异常，这些异常是心血管疾病的危险因素。使用SHR的同类基因和转基因模型已被证明是成功的分离核基因变异，有助于增加血压和生化特征的代谢综合征在实验性高血压。最近，有人假设线粒体基因组的变异也可能在高血压、代谢综合征和包括2型糖尿病在内的相关疾病中发挥重要作用。然而，尽管人类研究的结果诱人，但在测试线粒体DNA（mtDNA）假说方面的进展有限，因为很少有动物模型可用于直接研究mtDNA变体对代谢综合征的生化或血流动力学特征的影响。为了解决这个问题，我们已经推导出了具有相同核基因组但不同线粒体基因组的SHR的新模型。例如，SHR-mtBN共塑株携带SHR背景上BN株的线粒体基因组，并且与SHR祖株在遗传上相同，除了它们的线粒体基因组中的确定差异。使用这些新模型，我们还确定了与线粒体功能，胰岛素敏感性和代谢综合征生化特征相关的mtDNA序列变异。在目前的研究中，我们将利用这些独特的模型来直接研究线粒体DNA假说，并确定线粒体基因组中序列变异导致高血压和代谢综合征发病的分子和细胞机制。高血压通常与糖尿病和心脏病的多种危险因素的聚集有关，包括葡萄糖和脂肪代谢异常，血压升高糖尿病和心脏病的多种危险因素的这种聚集被称为代谢综合征，影响25%的普通人群和多达50%的高血压患者。该项目旨在研究影响代谢综合征发展的遗传因素，并最终帮助确定预防和治疗糖尿病和心血管疾病的新靶点。

DESCRIPTION (provided by applicant): Essential hypertension is frequently associated with the clustering of multiple risk factors for diabetes and cardiovascular disease including insulin resistance, dyslipidemia, as well as increased blood pressure. This clustering of multiple risk factors for heart disease and diabetes is often referred to as the metabolic syndrome and is reported to affect 25% of the general population and as many as 50% of patients with hypertension. It is well established that weight loss and exercise can be effective in ameliorating hypertension, diabetes, and the metabolic syndrome, however, such life style modifications are often difficult to achieve in clinical practice. Moreover, many patients with hypertension or obesity do not develop the metabolic syndrome or diabetes. Thus, it is hoped that the identification of genetic mechanisms that predispose patients to developing the hypertension metabolic syndrome will ultimately help guide development of new approaches to prevention and therapy. 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. The use of congenic and transgenic models of the SHR has proven to be successful in isolating nuclear gene variants that contribute to increased blood pressure and biochemical features of the metabolic syndrome in experimental hypertension. Recently, it has been hypothesized that variation in the mitochondrial genome may also play an important role in hypertension, the metabolic syndrome, and related disorders including type 2 diabetes. However, despite tantalizing results from human studies, progress in testing the mitochondria DNA (mtDNA) hypothesis has been limited because few animal models have been available for directly investigating the effects of mtDNA variants on biochemical or hemodynamic features of the metabolic syndrome. To address this problem, we have derived novel models of the SHR with identical nuclear genomes but different mitochondrial genomes. For example, the SHR-mtBN conplastic strain carries the mitochondrial genome of the BN strain on the SHR background and is genetically identical to the SHR progenitor strain except for defined differences in their mitochondrial genomes. Using these new models, we have also identified sequence variants in mtDNA linked to effects on mitochondrial function, insulin sensitivity, and biochemical features of the metabolic syndrome. In the current studies, we will capitalize on these unique models to directly investigate the mtDNA hypothesis and determine the molecular and cellular mechanisms whereby sequence variation in the mitochondrial genome contributes to the pathogenesis of hypertension and the metabolic syndrome Hypertension is frequently associated with the clustering of multiple risk factors for diabetes and heart disease including abnormalities in glucose and fat metabolism as well as increased blood pressure. This clustering of multiple risk factors for diabetes and heart disease is referred to as the metabolic syndrome and affects 25% of the general population and as many as 50% of patients with hypertension. This project is designed to investigate genetic factors that influence the development of the metabolic syndrome and ultimately help identify new targets for prevention and treatment of diabetes and cardiovascular disease.