Aldosterone Synthase & Hypertension

醛固酮合酶

基本信息

批准号：
9052214
负责人：
ASHOK KUMAR
金额：
$ 22.24万
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 2016-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9052214
关键词：
Adipose tissue Adrenal Cortex Adrenal Glands Aldosterone Alleles Anabolism Angiotensin II Animals Base Sequence Binding Binding Sites Biological Blood Pressure Brain CYP11B2 gene 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 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）在血压调节中起重要作用。醛固酮的不当增加会导致与年龄相关的血压和其他心血管问题的增加。醛固酮是在肾上腺皮质的ZG中合成的，醛固酮合酶是其生物合成中的速率限制酶。醛固酮合酶由CYP11B2基因编码，人类基因在其启动子中的T/C多态性位于-344。流行病学研究表明，CYP11B2基因的变体-344T与高血压和心肌肥大有关。人CYP11B2基因在其1 kb的启动子中具有三个SNP，它们几乎完全连接平衡。这些SNP为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与含有单倍型的单倍型的动物相比，含有单倍型的肾上腺素的小鼠在肾上腺和肾脏中的HCYP11B2 mRNA水平增加。与单倍型-II相比，含有HCYP11B2基因的单倍型-I的转基因小鼠的血压增加。单倍型-I。与-344C等位基因相比，醛固酮产生调节调节的长期变化导致含-344T等位基因的人体受试者的血压和心血管并发症的增加。这些转基因小鼠将用于了解这些单倍型对男性和雌性动物血压调节的作用。转基因小鼠还可以用于开发新的治疗试剂，以降低血压和心血管并发症。