Inflammatory factors, genes and stress induced pressure natriuresis in youth

描述（由申请方提供）：应激诱导的压力性尿钠排泄受损定义为在长期应激期间血压（BP）升高，但尿钠排泄（UNaV）没有充分代偿性增加，从而导致收缩压（SBP）恢复至应激前水平。对动物模型和人类受试者的研究表明，压力下血压的升高显著依赖于白细胞介素-6（IL-6）。IL-6是一种多功能细胞因子，其通过包含两个亚基（IL-6受体（IL-6 R）和gp 130细胞因子信号转导子（gp 130））的受体起作用，并释放C-反应蛋白（CRP）。因此，主要目标是确定IL-6通路对血压正常青年在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：全面分析遗传变异性和测量循环水平。因此，本文的具体目的是检验以下假设：1.与没有IL-6通路基因的青少年相比，具有不利基因型或单倍型的青少年将显示出减少的应激诱导的UNaV增加和应激后SBP恢复延迟。2.应激后血浆IL-6和CRP水平与青年应激诱发的UNaV呈负相关，但与青年应激后SBP恢复呈正相关。将对共计500名15-19岁的受试者进行研究，其中包括同等数量的白人和黑人、男孩和女孩。所有受试者之前都接受过延长应激方案（包括恢复期）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、IL 6 R、gp 130和CRP基因的功能SNP。将收集这些青少年父母的颊细胞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例受试者的子样本中检查IL-6和CRP的血浆水平。这项研究将为应激、炎症和遗传之间的相互作用及其在原发性高血压发病机制中的作用提供新的见解。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风险因素提供新的方法。

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.