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会导致高血压，称为神经源性高血压。现在是合理的，我们的假设是神经源性高血压是一个主要原因，是一种“缺失的联系”，在高血压的发展中。因此，了解神经源性高血压的分子框架将有助于改善疾病治疗或治愈的治疗以及预测性诊断。我们先前的结果将目前的提案重点放在细胞核Solitarius（NTS）中的A2 Catecholamin能神经元上。 A2神经元调节血压设定点，与对压力感受器反射功能或增益的任何影响无关。 A2细胞还与我们对NTS对高血压的分子自适应反应以及NTS反应的基因调节网络计算模型的转录分析研究有关。本提案将表征A2细胞对急性持续高血压的反应，并使用预测建模来了解A2细胞性质的复杂改变和介导其适应性反应的分子过程。我们还将研究与血压控制有关的功能连接的A2神经元的特定子集的网络行为。我们将使用迭代实验/计算生物学方法来构建和分析A2神经元功能连接的基因子集的详细基因调节网络模型。这些网络模型将预测血压设定点控制的A2神经元的适应性机制，尤其是响应急性持续性高血压。这些预测将通过体内遗传操作以及分子和生理测定法进行测试，以揭示对维持正常血压至关重要的分子相互作用。