Inflammatory factors, genes and stress induced pressure natriuresis in youth

描述（由申请人提供）：受损的应激性压力性尿钠症被定义为在长期应激期间血压（BP）升高，但尿钠排泄（UNaV）没有足够的代偿性增加，从而导致收缩压（SBP）恢复到应激前水平。动物模型和人体实验表明，应激下血压升高明显依赖于白细胞介素-6 （IL-6）。IL-6是一种多功能细胞因子，通过IL-6受体（IL-6R）和gp130细胞因子信号换能器（gp130）两个亚基组成的受体起作用，并释放c反应蛋白（CRP）。因此，主要目的是确定IL-6途径在正常血压青年应激下钠稳态和血压动态调节中的作用。为了实现这一目标，本研究将采取两种方法：遗传变异的综合分析和循环水平的测量。因此，具体目的是检验以下假设：1。与没有IL-6通路基因型或单倍型的年轻人相比，具有不利基因型或单倍型的年轻人在应激诱导的UNaV增加和应激后的收缩压恢复延迟方面会有所减少。2. 应激反应的血浆IL-6和CRP水平与青年应激诱导的UNaV呈负相关，但与青年应激后收缩压恢复呈正相关。共有500名年龄在15-19岁之间的受试者将被研究，其中白人和黑人、男孩和女孩的人数相等。所有受试者之前都接受了延长应激协议的测试，包括一段恢复期。在这些受试者中，将使用标记SNP和单倍型方法系统地检测IL-6和CRP基因的单核苷酸多态性。还将研究IL-6、IL6R、gp130和CRP基因的功能snp。将收集这些年轻人父母的颊细胞DNA，以便进行(1)单倍型重建和分析，(2)传播不平衡测试（tdt）。将在109名受试者的亚样本中检测IL-6和CRP的血浆水平。这项研究将为应激、炎症和遗传学之间的相互作用以及它们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风险因素提供一种新的方法。

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.