Theorectal and Experimental Investigations of Microcirculatory Signaling

微循环信号传导的理论和实验研究

基本信息

批准号：
7640676
负责人：
Nikolaos Michael Tsoukias
金额：
$ 28万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640676
关键词：
Affect Angiotensins Animal Model Animals Area Arginine Atherosclerosis Blood Pressure Blood Vessels Cause of Death Chronic Complex Computer Simulation Data Development Disease Equilibrium Event Feedback Functional disorder Goals Health Heart Diseases Homeostasis Hypertension In Vitro Intervention Investigation Kidney Kidney Failure Knowledge Laboratories Lead Life Link Microcirculation Modeling Molecular Profiling Nitric Oxide Ouabain Outcome Oxidative Stress Peripheral Pharmacy (field)Phenotype Physiological Physiology Play Population Positioning Attribute Predisposition Public Health Publications Pump Rattus Regulation Relaxation Renal function Renin-Angiotensin System Research Research Proposals Resistance Role Second Messenger Systems Series Signal Pathway Signal Transduction Signal Transduction Pathway Sodium Chloride Sodium-Calcium Exchanger Solid Stroke System Testing Theoretical Studies Theoretical model Therapeutic Tissues Translating Vascular resistance Work base biological systems cardiovascular disorder risk cardiovascular risk factor clinical practice effective therapy experience functional restoration improved in vitro Model inhibitor/antagonist innovation insight interest mathematical model model development normotensive novel strategies novel therapeutics protein expression research study response salt intake salt sensitive second messenger skills

项目摘要

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.

描述（由申请人提供）：血压对盐摄入量的敏感性出现在高血压患者和正常血压患者中，并且是一个主要的健康问题，因为它与心血管风险增加相关。先前的研究表明 L-精氨酸-一氧化氮 (NO) 系统在盐敏感性中发挥着核心作用。尽管先前做出了重大贡献，但有关 NO 在血管张力调节中的作用的基本问题仍未得到解答，这阻碍了当前优化现有干预措施和/或开发新治疗策略的努力。因此，本研究计划旨在填补对调节血管阻力机制的理解的重要空白，并将这些知识转化为临床可测试的假设，以改善高血压的治疗实践。本研究的中心假设是，血管阻力的调节是由 Ca2+ 和 NO 依赖性信号通路的非线性相互作用产生的。 NO/Ca2+动力学的改变导致盐敏感性高血压的微循环出现不同的表型。在这项研究中，我们采用理论模型和体外实验的创新协同方法来阐明微循环中的信号传导机制。数学模型在细胞水平上整合了生物物理详细机制，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，指导盐敏感性新型治疗策略的开发。体外实验研究有助于模型开发和测试模型生成的假设。在盐敏感性高血压动物模型中评估微循环表型和血管反应性。评估 NO 刺激与血管紧张素系统抑制或 Ca2+ 稳态效应器相结合的协同策略恢复正常血管功能的能力。相关性：盐摄入量会影响很大一部分人群的血压水平。这种情况被称为盐敏感性，是一个重大的公共卫生问题，因为它与心血管疾病的风险增加有关。在这项研究中，我们利用一种结合计算模型和实验的新方法来研究盐摄入量与血压之间的联系机制。初步结果表明，现有药物的组合可以对恢复微循环功能产生有益的作用，并将在高血压动物中进行测试。