Inflammatory factors, genes and stress induced pressure natriuresis in youth

炎症因素、基因和应激诱发的青少年压力尿钠

基本信息

批准号：
7282748
负责人：
HAIDONG ZHU
金额：
$ 14.27万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-15 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7282748
关键词：
Acute-Phase Proteins Affect Age Angiotensin II Angiotensins Animal Model Arousal Behavioral Blood Pressure C-reactive protein Cells Cytokine Signaling DNA Development Elevation Essential Hypertension Excretory function Exposure to Genes Genetic Genetic Variation Genotype Goals Haplotypes High Blood Pressure IL6 gene Individual Inflammation Inflammatory Interleukin 6 Receptor Interleukin-6 Measurement Modeling Natriuresis Numbers Parents Pathogenesis Pathway interactions Physiological Plasma Play Process Production Protein C Protocols documentation Recovery Regulation Renin-Angiotensin System Research Risk Factors Role Signal Transduction Single Nucleotide Polymorphism Sodium Stress Sympathetic Nervous System Testing Theoretical model Translations Youth blood pressure regulation boys cytokine cytokine receptor gp130 genetic analysis girls human subject insight normotensive novel pressure receptor reconstruction response transmission process urinary

项目摘要

DESCRIPTION (provided by applicant): Impaired stress-induced pressure natriuresis is defined as an increase in blood pressure (BP) during a period of extended stress without an adequate compensatory increase in urinary sodium excretion (UNaV) to contribute to the return of systolic BP (SBP) to pre-stress levels. Studies on animal models and human subjects reveal that BP increase under stress depends significantly on interleukin-6 (IL-6). IL-6 is a multi- functional cytokine that acts through a receptor comprising two subunits, IL-6 receptor (IL-6R) and gp130 cytokine signal transducer (gp130), and releases C-reactive protein (CRP). The main goal thus is to determine the role of the IL-6 pathway on the dynamic regulation of sodium homeostasis and BP under stress in normotensive youth. To achieve this goal, this proposed study will take two approaches: comprehensive analyses of genetic variability and measurements of circulating levels. Therefore, the specific aims are to test the following hypotheses: 1. Youth with unfavorable genotypes or haplotypes of the genes in the IL-6 pathway compared to those without will show a reduced stress-induced increase in UNaV and delayed SBP recovery following stress. 2. Plasma IL-6 and CRP levels in response to stress will be inversely related to stress-induced UNaV in youth, but positively related to recovery SBP following stress in youth. A total of 500 subjects aged 15-19 yrs will be studied which include an equal number of whites and blacks, boys and girls. All subjects have been previously tested with an extended stress protocol including a recovery period. Single nucleotide polymorphisms (SNPs) in the IL-6 and CRP genes will be systematically examined in these subjects using tagging SNP and haplotype approaches. Functional SNPs of the IL-6, IL6R, gp130 and CRP genes will also be studied. Buccal cell DNA from the parents of these youth will be collected to facilitate (1) haplotype reconstruction and analyses and (2) transmission disequilibrium tests (TDTs). Plasma levels of IL-6 and CRP will be examined in a subsample of 109 subjects. This research will provide novel insight into the interactions between stress, inflammation, and genetics, and their contribution to the pathogenesis of essential hypertension. The project aims to investigate the influence of inflammation, stress and genes on the body's ability to release sodium. Understanding the connections between stress, inflammation, and genes will provide a fresh approach into evaluating risk factors for high blood pressure.

描述（由申请人提供）：压力引起的压力性尿钠排泄受损被定义为在长期压力期间血压（BP）升高，而尿钠排泄（UNaV）没有足够的代偿性增加以有助于收缩压的恢复(SBP) 至预应力水平。对动物模型和人类受试者的研究表明，压力下血压升高很大程度上取决于白细胞介素 6 (IL-6)。 IL-6是一种多功能细胞因子，通过包含两个亚基IL-6受体(IL-6R)和gp130细胞因子信号转导器(gp130)的受体发挥作用，并释放C反应蛋白(CRP)。因此，主要目标是确定 IL-6 通路对血压正常的青少年压力下钠稳态和血压动态调节的作用。为了实现这一目标，这项拟议的研究将采取两种方法：遗传变异性的综合分析和循环水平的测量。因此，具体目标是检验以下假设： 1. 与没有 IL-6 途径基因型或单倍型的青少年相比，具有不利基因型或 IL-6 途径基因单倍型的青少年将表现出应激引起的 UNaV 增加减少，并在应激后延迟 SBP 恢复。 2. 应激反应中的血浆 IL-6 和 CRP 水平与青少年应激诱发的 UNaV 呈负相关，但与青少年应激后 SBP 的恢复呈正相关。总共 500 名 15 至 19 岁的受试者将接受研究，其中包括同等数量的白人和黑人、男孩和女孩。所有受试者之前都经过了包括恢复期在内的延长压力方案的测试。将使用标记 SNP 和单倍型方法在这些受试者中系统地检查 IL-6 和 CRP 基因中的单核苷酸多态性 (SNP)。还将研究 IL-6、IL6R、gp130 和 CRP 基因的功能 SNP。将收集这些青少年父母的口腔细胞 DNA，以促进 (1) 单倍型重建和分析以及 (2) 传递不平衡测试 (TDT)。将在 109 名受试者的子样本中检查 IL-6 和 CRP 的血浆水平。这项研究将为压力、炎症和遗传之间的相互作用及其对原发性高血压发病机制的贡献提供新的见解。该项目旨在研究炎症、压力和基因对人体释放钠的能力的影响。了解压力、炎症和基因之间的联系将为评估高血压的危险因素提供一种新的方法。