New Experimental Models of Hypertension

新的高血压实验模型

• 批准号: 7761674
• 负责人: THEODORE W KURTZ
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7761674
• 关键词: Address; Affect; Amino Acid Substitution; Animal Model; Behavior Therapy; Biochemical; Blood Pressure; Body Weight decreased; Candidate Disease Gene; Carbohydrates; Cardiovascular Diseases; Cell Line; DNA; Development; Diabetes Mellitus; Disease; Dyslipidemias; Essential Hypertension; Exercise; Exhibits; Experimental Models; Gene Expression; General Population; Genetic; Genetic Models; Genetic Variation; Genome; Glucose; Haplotypes; Heart Diseases; Hour; Human; Hypertension; Inbred SHR Rats; Inherited; Insulin Resistance; Link; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Norway; Nuclear; Obesity; Oxidative Phosphorylation; Pathogenesis; Patients; Phenotype; Play; Positioning Attribute; Prevention; Prevention approach; Prevention therapy; Proteins; Rattus norvegicus; Reporting; Risk; Risk Factors; Rodent; Role; Techniques; Testing; Transgenic Model; Variant; base; clinical practice; congenic; cytochrome c oxidase; design; glucose metabolism; hemodynamics; insulin sensitivity; interest; lipid metabolism; mitochondrial genome; novel; novel strategies; progenitor

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.

描述（由申请人提供）：基本高血压通常与糖尿病和心血管疾病多种危险因素的聚类有关，包括胰岛素抵抗，血脂异常以及血压升高。多种心脏病和糖尿病危险因素的聚类通常称为代谢综合征，据报道会影响25％的普通人群和多达50％的高血压患者。众所周知，体重减轻和运动可以有效地改善高血压，糖尿病和代谢综合征，但是，这种生活方式的改变通常在临床实践中很难实现。此外，许多患有高血压或肥胖症的患者不会发展代谢综合征或糖尿病。因此，希望能够鉴定出使患者倾向于发展高血压代谢综合征的遗传机制，最终将有助于指导开发新的预防和治疗方法。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。事实证明，SHR的先天性和转基因模型的使用在隔离核基因变异方面已成功，这些变体有助于增加体重和代谢综合征在实验性高血压中的生化特征。最近，已经假设线粒体基因组的变异在高血压，代谢综合征和包括2型糖尿病在内的相关疾病中也可能起重要作用。然而，尽管人类研究的诱人结果，但测试线粒体DNA（mtDNA）假设的进展受到限制，因为很少有动物模型可直接研究MTDNA变异型对代谢综合征的生化或血液动力学特征的影响。为了解决这个问题，我们以相同的核基因组来得出SHR的新型模型，但线粒体基因组不同。例如，SHR-MTBN构型菌株在SHR背景上带有BN菌株的线粒体基因组，并且在遗传上与SHR祖细胞菌株相同，除了其线粒体基因组的确定差异。使用这些新模型，我们还确定了MTDNA中的序列变体，这些变体与对线粒体功能，胰岛素敏感性和代谢综合征的生化特征的影响相关。在当前的研究中，我们将利用这些独特的模型直接研究mTDNA假说，并确定分子和细胞机制，从而使线粒体基因组的序列变化有助于高血压的发病机理，而代谢综合征高血压通常与糖尿病和心脏病的多重危险因素以及伴有临床症的症状以及gluc症以及glucnorsy and glucnorsy and Gluc normans glucsity and Morge and glucnormens and glucnormens and glucnormens and glucnormens and glucnorments and glucs normans glucs型相关。多种糖尿病和心脏病危险因素的聚类称为代谢综合征，影响了普通人群的25％，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，并最终有助于确定预防和治疗糖尿病和心血管疾病的新目标。