Modeling Central Autonomic Regulatory Network Adaptation to Hypertension

中央自主调节网络对高血压的适应建模

基本信息

批准号：
8843930
负责人：
JAMES SCHWABER
金额：
$ 59.2万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843930
关键词：
Acute Affect Animal Model Automobile Driving Baroreflex Behavior Binding Biological Assay Blood Pressure Brain Stem Cardiovascular system Catecholamines Cells Characteristics Complex Computational Biology Computer Simulation Data Data Set Decision Trees Development Diagnostic Disease Elements Essential Hypertension Gene Expression Gene Expression Regulation Genes Hypertension Hypothalamic structure Ion Channel Lentivirus Vector Link Measures Mediating Methods Modeling Molecular Molecular Analysis Molecular Profiling Multivariate Analysis Neurons Nucleus solitarius Pathway Analysis Phenotype Phenylephrine Physiological Population Prevalence Process Property Recombinants Regulation Regulator Genes Regulatory Element Rest Sampling Series Signal Transduction Structure System Technology Testing Therapeutic Time Transcript Viral Vector Work base blood pressure regulation computational network modeling design gene interaction genetic manipulation improved in vivo innovation inward rectifier potassium channel laser capture microdissection network models neurogenic hypertension normotensive novel predictive modeling research study response

项目摘要

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.

描述（由申请人提供）：最近的证据表明，血压设定点的神经元控制的改变可能导致高血压，称为神经源性高血压。现在，我们的假设是，神经源性高血压是高血压发展的一个主要原因，是高血压发展中的一个“缺失环节”，这一点似乎是合理的。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诊断的发展。我们之前的结果主要集中在孤束核 (NTS) 中的 A2 儿茶酚胺能神经元上。 A2 神经元调节血压设定点，不受对压力感受器反射功能或增益的任何影响。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也涉及 A2 细胞。本提案将描述 A2 细胞对急性持续性高血压的反应特征，并使用预测模型来了解 A2 细胞特性和介导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功能连接 A2 神经元特定子集的网络行为。我们将使用迭代实验/计算生物学方法构建和分析 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 神经元的血压设定点控制的适应性机制，特别是响应急性持续性高血压。这些预测将通过体内基因操作以及分子和生理测定进行测试，以揭示对维持正常血压至关重要的分子相互作用。