Central Autonomic Orchestration of Blood Pressure

描述(由申请人提供)：我们的建议试图了解大脑对血压输入的适应性反应，特别是血管紧张素II(Ang11)在这种反应中的作用。我们将集中于孤束核(NTS)，它在心血管功能的中枢调节中发挥关键作用，以及Ang II AT1受体(AT1R)，它在大脑内作用于增加交感神经流出和血压，这在高血压中起主要作用。中央控制功能具有高度的适应性，例如对血管紧张素转换酶II，以及对血压输入的持续变化的反应。这些过程通过细胞内信号机制改变细胞状态和未来的输入输出神经元反应，这些信号机制对膜电行为和神经递质输出具有中长期的影响。在本研究中，我们将使用AT1受体和急性高血压作为干扰来研究这些适应过程的调节，以激活NTS的适应过程。尽管NTS Ang II系统在高血压中的生理学已被很好地建立，但中枢控制多动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AT1R启动的信号过程和转录调控网络活动，改变NTS的状态及其输出神经电生理。本提案的做法涉及将这些过程作为一个单一的蜂窝系统一起进行审查。这一复杂系统的行为涉及使用定性推理难以预测的动态相互作用，因此需要在系统级别上采用经过实验验证的计算建模方法。这些方法对假设的产生将是无价的，并将为系统比较通过实验收集的数据提供一个框架。为了研究这些过程，本项目提出了三个具体目标：目标1模拟AT1R对基因调控的影响，以及产生基因和蛋白质表达以及酶活性变化的多水平信号-核环。其目的是开发适合于计算机模拟研究的数学模型，并通过实验验证预测的过程迭代地精炼这些模型。目的2模拟AT1R从AIM 1激活的适应过程在急性高血压患者的NTS对AT1R反应中的作用。方法是对这一角色中涉及的TF和信号活动做出具体的预测，并通过实验测试这些预测，改进模型并揭示过程中涉及的关键活动。目的3模拟AT1R对膜通道动力学的影响，导致放电行为的改变，以及AT1R激活引起的基因表达改变对该系统和行为的影响。这种方法是在生理反应所涉及的分子过程的影响水平上测试这些预测，包括来自基因调控反应的反馈。

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.