Aldosterone Synthase & Hypertension

醛固酮合酶

基本信息

批准号：
8837685
负责人：
ASHOK KUMAR
金额：
$ 62.29万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8837685
关键词：
Adipose tissue Adrenal Cortex Adrenal Glands Aldosterone Aldosterone Synthase Alleles Anabolism Angiotensin II Animals Base Sequence Binding Binding Sites Biological Blood Pressure Brain Cardiovascular Diseases Cardiovascular system Caucasians Cells Cholesterol Code Diet Elderly Enzymes Epidemiologic Studies Equilibrium Exons Fatty acid glycerol esters Female Genes Genetic Polymorphism Genomic DNA Haplotypes Health Heart failure Human Hypertension Hypertrophy In Vitro Introns Kidney Kidney Failure Knock-in Mouse Messenger RNA Molecular Mus Myocardial Myocardial Infarction Names Oligonucleotides Plasma Play Production Proteins Reagent Recombinants Regulation Renin-Angiotensin-Aldosterone System Reporter Reporter Genes Risk Factors Role SF1 Sodium Chloride Stroke Time Tissues Transcriptional Regulation Transfection Transgenic Animals Transgenic Mice Transgenic Organisms Untranslated Regions Variant Vascular Diseases age related aldosterone hypertension blood pressure reduction blood pressure regulation human subject in vivo male normotensive novel therapeutics promoter research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hypertension is a serious risk factor for myocardial infarction, heart failure, vascular disease, stroke, and renal failure. The renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure. Inappropriate increase of aldosterone causes age-related increase in blood pressure and other cardiovascular problems. Aldosterone is synthesized in the ZG of the adrenal cortex and aldosterone synthase is the rate limiting enzyme in its biosynthesis. Aldosterone synthase is coded by Cyp11B2 gene and the human gene has a T/C polymorphism located at -344 in its promoter. Epidemiological studies have suggested that variant -344T of Cyp11B2 gene is associated with hypertension and myocardial hypertrophy. Human Cyp11B2 gene has three SNPs in 1 Kb of its promoter that are in almost complete linkage dis-equilibrium. These SNPs are rs1799998 (T/C at -344), rs10087214 (C/T at -470), rs28659182 (C/A at -663). Thus variant -344T almost always occurs with variants -470C, -663A (named haplotype-I, and variant -344C almost always occurs with variants, - 470T, -663T (named haplotype-II). We have generated transgenic mice by knocking in hCyp11B2 gene containing either haplotype-I or haplotype-II at the HPRT locus. Transgenic mice containing haplotype-I have increased hCyp11B2 mRNA level in the adrenals and kidneys as compared to transgenic animals containing haplotype-II. In addition, male transgenic animals containing haplotype-I have increased blood pressure as compared to transgenic animals containing haplotype-II of hCyp11B2 gene. High salt (4% NaCl diet) and angiotensin-II administration increases blood pressure in transgenic mice containing haplotype-I of hCyp11B2 gene as compared to haplotype-II. Therefore, our hypothesis is that transcription factors bind strongly to the nucleotide sequence of hCyp11B2 gene containing haplotype-I as compared to haplotype-II, and increase its expression. This increases tissue or plasma aldosterone level in human subjects containing haplotype-I. The long term consequence of altered regulation of aldosterone production leads to an increase in blood pressure and cardiovascular complications in human subjects containing -344T allele as compared to -344C allele. These transgenic mice will be used to understand the role of these haplotypes on blood pressure regulation in male and female animals. Transgenic mice may also be used to develop new therapeutic reagents to reduce blood pressure and cardiovascular complications.

描述（由申请人提供）：高血压是心肌梗塞、心力衰竭、血管疾病、中风和肾衰竭的严重危险因素。肾素-血管紧张素-醛固酮系统（RAAS）在血压调节中发挥着重要作用。醛固酮的不当增加会导致与年龄相关的血压升高和其他心血管问题。醛固酮在肾上腺皮质的 ZG 中合成，醛固酮合酶是其生物合成的限速酶。醛固酮合酶由Cyp11B2基因编码，人类基因在其启动子中具有位于-344位的T/C多态性。流行病学研究提示Cyp11B2基因变异-344T与高血压、心肌肥厚有关。人Cyp11B2基因在其启动子的1Kb内有3个几乎完全连锁不平衡的SNP。这些SNP是rs1799998（T/C在-344）、rs10087214（C/T在-470）、rs28659182（C/A在-663）。因此，变体-344T几乎总是与变体-470C、-663A（称为单倍型-I）一起出现，变体-344C几乎总是与变体-470T、-663T（称为单倍型-II）一起出现。我们通过敲入产生了转基因小鼠HPRT 基因座上含有单倍型 I 或单倍型 II 的 hCyp11B2 基因。与含有单倍型-II的转基因动物相比，单倍型-I在肾上腺和肾脏中增加了hCyp11B2 mRNA水平。此外，与含有单倍型-II的hCyp11B2基因的转基因动物相比，含有单倍型-I的雄性转基因动物血压升高。高盐（4% NaCl 饮食）和血管紧张素 II 给药会增加含有单倍型 I 的转基因小鼠的血压hCyp11B2 基因与单倍型-II 相比，因此，我们的假设是，与单倍型-II 相比，转录因子与含有单倍型-I 的 hCyp11B2 基因的核苷酸序列强烈结合，并增加其表达，这增加了组织或血浆醛固酮水平。含有单倍型-I的人类受试者。与-344C等位基因相比，醛固酮产生调节改变的长期后果导致含有-344T等位基因的人类受试者血压和心血管并发症增加。这些转基因小鼠将用于了解这些单倍型对雄性和雌性动物血压调节的作用。转基因小鼠还可用于开发新的治疗试剂，以降低血压和心血管并发症。