Mechanisms of Central Autonomic Orchestration of Blood Pressure

中枢自主神经调节血压的机制

• 批准号: 7249575
• 负责人: BORIS N KHOLODENKO
• 金额: $ 29.05万
• 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/7249575
• 关键词: angiotensin /renin /aldosterone hypertension; angiotensin II; angiotensin receptor; blood pressure; cardiovascular function; computer simulation; enzyme activity; gene expression; genetic transcription; intracellular transport; mathematical model; membrane channels; model design /development; protein structure function; single cell analysis; solitary tract nucleus

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）：我们的提案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 (Angll) 在这种反应中的作用。我们将重点关注在心血管功能的中枢调节中发挥关键作用的孤束核 (NTS)，以及在大脑内发挥作用以增加交感神经流出和血压的血管紧张素 II AT1 受体 (AT1R)，这些作用在高血压中起主要作用。中央控制功能具有高度适应性，例如Ang II，并且还可以响应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，这些信号传导机制对膜电行为和神经递质输出具有中长期尺度的影响。在本研究中，我们将使用 AT1 受体和急性高血压作为激活 NTS 适应性过程的干扰来研究这些适应性过程的调节。尽管 NTS Ang II 系统在高血压中的生理学已十分成熟，但中枢控制过度活跃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过程，涉及 AT1R 启动的信号传导过程和转录调节网络活动，改变 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蜂窝系统一起检查。这个复杂系统的行为涉及动态交互，很难使用定性推理来预测，并且需要在系统级别上经过实验验证的计算建模方法。这些方法对于假设的生成非常有价值，并将为系统比较跨实验收集的数据提供框架。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 对基因调控和多级信号传导核环的影响，这些环路会产生基因和蛋白质表达以及酶活性的变化。目标方法是开发适合计算机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。目标 2 模拟了目标 1 中 AT1R 激活的适应性过程在急性高血压神经元适应初始时间过程中对 AT1R 的 NTS 反应中的作用。该方法是对参与该角色的 TF 和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。目标 3 模拟 AT1R 对膜通道动力学的影响，从而导致放电行为发生改变，以及响应 AT1R 激活而改变的基因表达对该系统和行为的影响。该方法是在对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。