Theorectal and Experimental Investigations of Microcirculatory Signaling

微循环信号传导的理论和实验研究

• 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
• 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

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）：高血压和正常敏化剂的血压敏感性均出现，并且代表了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，在盐敏感性中，L-精氨酸氮（NO）系统起着核心作用。尽管先前做出了重大贡献，但关于NO在血管音调调节中的作用的基本问题仍未得到答复，这阻碍了当前的努力，以优化可用的干预措施和/或制定新的治疗策略。因此，该研究建议旨在填补对调节血管抗性的机制的理解，并将这些知识转化为可临床检验的假设，以改善高血压治疗实践。这项研究的中心假设是，由Ca2+和无依赖性信号通路的非线性相互作用出现了血管抗性的调节。 NO/Ca2+动力学改变的盐敏感高压敏感性在微循环中有助于不同的表型。在这项研究中，我们遵循理论建模和体外实验的创新协同方法，以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的机制，以描述宏观组织水平的生理功能。总体目标是提供一个理论框架，该框架将指导盐敏感性中新型治疗策略的发展。体外实验研究有助于模型开发和测试模型产生的假设。在盐敏感高血压的动物模型中评估了微循环表型和血管反应性。评估了无刺激的协同策略，以及抑制血管紧张素系统或Ca2+稳态的效应因子的协同策略，以恢复正常血管功能的能力。 相关性：盐摄入会影响很大一部分人口的血压水平。这种疾病（称为盐敏感性）代表了一个主要的公共卫生问题，因为它与心血管疾病的风险增加有关。在这项研究中，我们利用一种新的方法将计算建模和实验结合起来，研究将盐摄入和血压联系起来的机制。初步结果表明，可用药物的组合可以在恢复微循环中具有有益的作用，并将在高血压动物中进行测试。