Theorectal and Experimental Investigations of Microcirculatory Signaling

说明(申请人提供)：高血压患者和血压正常者都会出现对盐摄取的血压敏感性，这是一个主要的健康问题，因为它与心血管风险增加有关。先前的研究表明，L-精氨酸-一氧化氮(NO)系统在盐敏感性中起着核心作用。尽管先前做出了重大贡献，但关于NO在调节血管张力中的作用的基本问题仍然没有得到回答，这阻碍了目前优化可用的干预措施和/或开发新的治疗策略的努力。因此，这项研究计划旨在填补在了解调节血管阻力的机制方面的一个重要空白，并将这一知识转化为临床可测试的假说，以改进高血压的治疗实践。这项研究的中心假设是，血管阻力的调节出现在钙离子和一氧化氮依赖的信号通路的非线性相互作用中。改变的NO/Ca~(2+)动力学有助于盐敏感型高血压患者微循环中不同的表型。在这项研究中，我们遵循理论建模和体外实验相结合的创新方法来阐明微循环中的信号机制。数学模型集成了细胞水平上的生物物理学的详细机制，以描述宏观组织水平上的生理功能。总体目标是提供一个理论框架，指导盐敏感性新治疗策略的发展。体外实验研究有助于模型开发和测试模型生成的假设。在盐敏感型高血压动物模型中评估了微循环表型和血管反应性。对NO刺激与抑制血管紧张素系统或钙稳态效应物的协同策略进行评估，以了解它们恢复正常血管功能的能力。 相关性：盐摄入量会影响很大比例人群的血压水平。这种情况被称为盐敏感，是一个重大的公共卫生问题，因为它与心血管疾病风险增加有关。在这项研究中，我们利用计算模型和实验相结合的新方法来研究盐摄入量和血压之间的联系机制。初步结果表明，现有药物的组合在恢复微循环功能方面可以起到有益的作用，并将在高血压动物身上进行测试。

DESCRIPTION (provided by applicant): Blood pressure sensitivity to salt intake appears in both hypertensives and normotensives and represents a major health problem as it is associated with increased cardiovascular risk. Prior investigations have suggested a central role for the L-arginine-nitric oxide (NO) system in salt sensitivity. Despite significant prior contributions, fundamental questions about the role of NO in the regulation of vascular tone remain unanswered and this impedes current efforts to optimize available interventions and/or develop new therapeutic strategies. Therefore, this research proposal aims to fill an important gap in the understanding of the mechanisms that regulate vascular resistance and to translate this knowledge into clinically testable hypotheses for improved therapeutic practice in hypertension. The central hypothesis of this study is that regulation of vascular resistance emerges from the nonlinear interaction of Ca2+ and NO-dependent signaling pathways. Altered NO/Ca2+ dynamics contribute to a different phenotype in the microcirculation of salt-sensitive hypertensives. In this study we follow an innovative synergistic approach of theoretical modeling and in vitro experimentation to elucidate signaling mechanisms in the microcirculation. Mathematical models integrate biophysically detailed mechanisms at the cellular level to describe physiological function at a macroscale tissue level. The overall goal is to provide a theoretical framework that will guide the development of novel therapeutic strategies in salt sensitivity. In vitro experimental studies assist in model development and test model generated hypotheses. Microcirculatory phenotype and vascular reactivity are assessed in an animal model of salt sensitive hypertension. Synergistic strategies of NO stimulation combined with inhibition of the angiotensin system or effectors of Ca2+ homeostasis are evaluated for their ability to restore normal vascular function. Relevance: Salt intake affects blood pressure levels in a large percentage of the population. This condition, referred to as salt sensitivity, represents a major public health problem as it is associated with an increased risk for cardiovascular disease. In this study we utilize a novel approach of combining computational modeling and experimentation to investigate the mechanisms that link salt intake and blood pressure. Preliminary results suggest that combination of available pharmaceutics can have beneficial effects in restoring function in the microcirculation and will be tested in hypertensive animals.