Modeling Central Autonomic Regulatory Network Adaptation to Hypertension

描述(由申请人提供)：最近的证据表明，神经元控制血压设定值的改变会导致高血压，称为神经源性高血压。现在看来，我们的假设是，神经原性高血压是高血压发展过程中的一个主要原因，一个“缺失的环节”。因此，了解神经源性高血压的分子框架将有助于改进该疾病的治疗或治愈以及预测性诊断的发展。我们以前的结果集中在孤束核(NTS)内的A2儿茶酚胺能神经元。A2神经元独立于压力感受器反射功能或增益的任何影响来调节血压设定值。A2细胞也被我们对NTS对高血压的分子适应性反应的转录谱研究以及我们的NTS反应的基因调控网络计算模型所牵连。本提案将描述A2细胞对急性持续性高血压的反应，并使用预测性建模来了解A2细胞特性和调节其适应性反应的分子过程的复杂变化。我们还将研究与血压控制相关的特定功能连接的A2神经元亚群的网络行为。我们将使用迭代的实验/计算生物学方法来构建和分析A2神经元功能连接子集的详细基因调控网络模型。这些网络模型将预测A2神经元在血压设定点控制下的适应机制，特别是在应对急性持续性高血压时。这些预测将通过体内遗传操作以及分子和生理分析来验证，以揭示对维持正常血压至关重要的分子相互作用。

DESCRIPTION (provided by applicant): Recent evidence indicates that alterations in the neuronal control of blood pressure set point can cause hypertension, termed neurogenic hypertension. It is now plausible, and our hypothesis, that neurogenic hypertension is a major cause, a "missing link", in development of hypertension. Thus, understanding the molecular framework for neurogenic hypertension will facilitate development of improved treatment or cure of the disease, and predictive diagnostics. Our previous results focus the present proposal on the A2 catecholaminergic neurons in the nucleus tractus solitarius (NTS). The A2 neurons regulate blood pressure set point independent of any effect on baroreceptor reflex function or gain. A2 cells were also implicated by our transcript profiling studies of the molecular adaptive response of the NTS to hypertension, and by our gene regulatory network computational models of the NTS response. The present proposal will characterize the responses of A2 cells to acute sustained hypertension and use predictive modeling to understand the complex alterations in A2 cellular properties and molecular processes mediating their adaptive responses. We will also study the network behavior of the specific subsets of functionally connected A2 neurons related to blood pressure control. We will build and analyze detailed gene regulatory network models of functionally connected subsets of A2 neurons using an iterative experimental/computational biology approach. These network models will predict the adaptive mechanisms of A2 neurons underlying blood pressure set point control in particular in response to acute sustained hypertension. The predictions will be tested by in vivo genetic manipulation and molecular and physiological assays to reveal molecular interactions critical to maintaining normal blood pressure.