Physiologic profiling of sGC genetic variants

sGC 遗传变异的生理学分析

基本信息

批准号：
8714033
负责人：
Christopher Holmes Newton-Cheh
金额：
$ 55.99万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-05 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714033
关键词：
3&apos Flanking Region Alleles Bacterial Artificial Chromosomes Biological Assay Blood Platelets Blood Pressure Blood Vessels Breathing Candidate Disease Gene Cardiovascular Diseases Cerebrovascular Disorders Chronic Kidney Failure Clinical Code Complex Cyclic GMP DNA Resequencing DNA Sequence Development Diastolic blood pressure Enzymes European Funding GUCY1A3 gene GUCY1B3 gene Gene Deletion Gene Expression General Population Genes Genetic Genetic Determinism Genetic Variation Genotype Goals Heart failure Heritability Homozygote Human Hypertension Individual Intervention Introns Investigation Kidney Kidney Diseases Link Marketing Messenger RNA Methods Minor Mus Mutation Myocardial Infarction Natriuretic Peptides Nitric Oxide Nucleotides PDE3A gene product Peptide Receptor Physiological Physiology Plasma Platelet Activation Platelet aggregation Population Prevalence Proteins Pulmonary artery structure Rattus Recruitment Activity Regulation Research Research Personnel Risk Factors Role Signal Pathway Signal Transduction Single Nucleotide Polymorphism Smooth Muscle Myocytes Sodium Chloride Soluble Guanylate Cyclase Source Stroke System Transcript Transfection Translating Translations Variant Vasodilation Work base blood pressure regulation enzyme activity experience genetic analysis genetic variant genome wide association study guanylate cyclase 1 healthy volunteer human NOS3 protein improved inhaled nitric oxide insight molecular phenotype novel programs public health relevance research study response trait

项目摘要

DESCRIPTION (provided by applicant): High blood pressure is a strong risk factor for cardiovascular, cerebrovascular, and kidney disease. Although highly heritable, the genetic basis of blood pressure variation in the general population has been poorly-defined. In preliminary work, a common genetic variant associated with blood pressure was identified at the GUCY1A3/GUCY1B3 locus, which encodes the alpha1 and beta1 subunit of soluble guanylate cyclase, an enzyme which synthesizes cGMP when activated by nitric oxide and which is abundantly expressed in the vasculature. Among up to 200,000 individuals of European ancestry, 58% of the population has two copies of a BP-raising allele. The overall goal of the proposed research program is to ascertain whether the GUCY1A3/GUCY1B3 genetic variant associated with blood pressure (or a closely linked variant) modulates expression of soluble guanylate cyclase alpha1 and/or beta1 subunits. In Aim 1, we seek to establish whether the association of BP with the SNP at the GUCY1A3/GUCY1B3 locus is likely to be determined by a difference in sGC activity. Inhaled nitric oxide will be administered to individuals with 0 or 2 copies of the BP-raising allele, and the impact of genotype on the ability of NO inhalation to increase plasma cGMP levels will be determined. In parallel experiments, platelet soluble guanylate cyclase subunit mRNA and protein levels, as well as enzyme activity and NO- inhabitable aggregation will be compared between genotypes. In Aim 2, genetic variants will be introduced into bacterial artificial chromosomes containing the human GUCY1A3/GUCY1B3 locus. Clones containing major and minor alleles will be introduced in vascular smooth muscle cells, and expression of the soluble guanylate cyclase alpha1 and beta1 subunits will be compared. The investigators' proposed use of detailed physiologic phenotyping and molecular characterization of the DNA sequence variation promises to yield fundamental insights into regulation of the GUCY1A3 and GUCY1B3 genes and to begin to better understand the role of nitric oxide-soluble guanylate cyclase-cGMP signaling in blood pressure regulation in the general population.

描述（由申请人提供）：高血压是心血管，脑血管和肾脏疾病的强大风险因素。尽管高度可遗传，但普通人群血压变化的遗传基础的定义很差。在初步工作中，在GuCy1a3/gucy1b3座位上鉴定了一种与血压相关的常见遗传变异，该酶编码了可溶性鸟烯酸鸟酯环化酶的alpha1和beta1亚基，这是一种酶，一种酶，该酶通过氧化氧化物和表达含量表达的氧化含量时，该酶合成CGMP。在多达200,000个欧洲血统的人中，有58％的人口有两份BP升级等位基因。提出的研究计划的总体目标是确定与血压（或紧密联系的变体）相关的GUCY1A3/GUCY1B3遗传变异是否会调节可溶性鸟苷酸环化酶alpha1和/或beta1亚基的表达。在AIM 1中，我们试图确定在GUCY1A3/GUCY1B3基因座上BP与SNP的关联是否可能取决于SGC活性的差异。吸入一氧化氮将被施用给具有0或2份BP-RAISERELERELE的个体，并将确定基因型对NO吸入增加等离子体CGMP水平的能力的影响。在平行的实验中，将比较基因型之间的血小板可溶性鸟苷酸环化酶亚基mRNA和蛋白质水平以及酶活性和无居住的聚集。在AIM 2中，遗传变异将被引入包含人类GUCY1A3/GUCY1B3基因座的细菌人造染色体中。将在血管平滑肌细胞中引入含有主要和小等位基因的克隆，并将比较可溶性鸟苷酸环化酶α1和Beta1亚基的表达。研究人员提出了对DNA序列变化的详细生理表型和分子表征的使用，有望在调节GUCY1A3和GUCY1B3基因的调控中产生基本的见解，并开始更好地了解硝酸氧化物氧化物氧化物氧化物氧化物氧化物氧化圭甲酰化环境磷酸甘氨酸磷酸甘氨酸磷酸甘油儿CGMP信号在血液压力中的调节。