Mechanisms of Central Autonomic Orchestration of Blood Pressure

中枢自主神经调节血压的机制

• 批准号: 7290920
• 负责人: BORIS N KHOLODENKO
• 金额: $ 27.46万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-27 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290920
• 关键词: Acute; Angiotensin II; Behavior; Blood Pressure; Brain; Cardiovascular system; Cell Nucleus; Classification; Complex; Computer Simulation; Data; Feedback; Fire - disasters; Future; Gene Expression; Gene Expression Regulation; Gene Proteins; Generations; Hyperactive behavior; Hypertension; Ion Channel; Kinetics; Membrane; Modeling; Molecular; Neurons; Neurotransmitters; Nucleus solitarius; Output; Performance; Personal Satisfaction; Physiological; Physiology; Play; Process; Receptor Activation; Regulation; Regulator Genes; Role; Signal Transduction; System; Testing; Time; base; computerized data processing; enzyme activity; improved; mathematical model; protein expression; receptor; research study; response; role model; simulation

DESCRIPTION (provided by applicant): Our proposal seeks to understand the adaptive response of the brain to blood pressure inputs, and in particular the role of Angiotensin II (Angll) in this response. We will focus on the nucleus tractus solitarius (NTS) which plays a key role in the central regulation of cardiovascular performance, and on the Ang II AT1 receptor (AT1R) which acts within the brain to increase sympathetic outflow and blood pressure, effects which play a major role in hypertension. The central control function is highly adaptive, for example to Ang II, and also in response to sustained changes in blood pressure inputs. These processes alter the cellular state and future input-output neuronal responses via intracellular signaling mechanisms that have intermediate- and long-time scale influences on membrane electrical behavior and neurotransmitter outputs. In the present study, we will study these adaptive processes regulation using the AT1 receptor and acute hypertension as disturbances to activate NTS adaptive processes. Although the physiology of the NTS Ang II system in hypertension is well established, the cellular and molecular basis of central control hyperactivity is not understood. It is clear that it is a complex, multifactorial process involving AT1R initiated signaling processes and transcriptional regulatory network activities that alters the state of NTS and its output neuroelectrophysiology. The approach of the present proposal involves examining these processes together as a single cellular system. The behavior of this complex system involves dynamic interactions that are difficult to predict using qualitative reasoning and there is a need for experimentally validated computational modeling approaches at the systems level. These approaches will be invaluable in generation of hypotheses and will provide a framework for the systematic comparison of data collected across experiments. In order to study these processes the present project proposes three specific Aims: Aim 1 models the influences of AT1R on gene regulation and the multi-level signaling-nucleus loop that produce changes in gene and protein expression and enzyme activities. The approach of the aim is to develop mathematical models suitable for in silico simulation study, and to refine these models iteratively by a process of testing predictions experimentally. Aim 2 models the role of the AT1R activated adaptive processes from Aim 1 in the NTS response to AT1R in acute hypertension over the initial time course of neuronal adaptation. The approach is to make specific predictions as to TF and signaling activities involved in this role, and to test these predictions experimentally, improving the model and revealing key activities involved in the process. Aim 3 models the AT1R influences on membrane channel kinetics resulting in modified firing behavior, and the effects of altered gene expression in response to AT1R activation on this system and behavior. The approach is to test these predictions at the level of effects on molecular processes involved in the physiological response, including feedback from gene regulatory responses.

描述（由申请人提供）： 我们的建议旨在了解大脑对血压输入的适应性反应，特别是血管紧张素II（AngII）在这种反应中的作用。我们将重点关注孤束核（NTS），它在心血管功能的中枢调节中起着关键作用，以及在脑内起作用以增加交感神经流出和血压的血管紧张素II AT 1受体（AT 1 R），这些作用在高血压中起着重要作用。中央控制功能是高度适应性的，例如对Ang II，并且还响应于血压输入的持续变化。这些过程通过细胞内信号传导机制改变细胞状态和未来的输入-输出神经元反应，所述细胞内信号传导机制对膜电行为和神经递质输出具有中期和长期尺度的影响。在本研究中，我们将研究这些适应性过程的调节使用AT 1受体和急性高血压作为干扰激活NTS适应性过程。虽然高血压中NTS血管紧张素II系统的生理学已被很好地建立，但中枢控制亢进的细胞和分子基础尚不清楚。很明显，这是一个复杂的，多因素的过程，涉及AT 1 R启动的信号传导过程和转录调控网络活动，改变了NTS的状态及其输出神经电生理学。本提案的方法涉及将这些过程作为单个细胞系统一起检查。这个复杂的系统的行为涉及到动态的相互作用，很难预测使用定性推理，并有必要在系统级的实验验证的计算建模方法。这些方法将是非常宝贵的生成的假设，并将提供一个框架，系统地比较收集的数据在实验中。为了研究这些过程，本项目提出了三个具体的目标：目标1模型AT 1 R对基因调控的影响和多层次的信号核环，产生基因和蛋白质表达和酶活性的变化。该方法的目的是开发适合于在硅片模拟研究的数学模型，并通过实验测试预测的过程迭代地完善这些模型。目的2模型的作用，AT 1 R激活的适应性过程，从目的1在急性高血压的NTS响应AT 1 R在最初的时间过程中的神经元适应。该方法是对TF和参与该作用的信号活动进行具体预测，并通过实验测试这些预测，改进模型并揭示该过程中涉及的关键活动。目的3模拟AT 1 R对膜通道动力学的影响，从而导致修改的发射行为，以及响应于AT 1 R激活的基因表达改变对此系统和行为的影响。该方法是测试这些预测的水平上的影响，参与生理反应的分子过程，包括从基因调控反应的反馈。