Integrated Modeling of Adaptive Neuronal Regulation

自适应神经元调节的集成建模

基本信息

批准号：
8248271
负责人：
JAMES SCHWABER
金额：
$ 37.86万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-08 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248271
关键词：
Address Affect Angiotensin II Baroreflex Binding Bioinformatics Biology Biophysical Process Brain Brain Stem Complex Computer Simulation Data Development Disease Disease Progression Electrophysiology (science)Environment Enzymes Gene Expression Gene Expression Regulation Gene Targeting Generations Genes Goals Health Homeostasis Hypertension Immediate-Early Genes Ion Channel Maintenance Measurement Mediating Membrane Messenger RNA Methods Modeling Molecular Molecular Analysis Neuromodulator Neurons Nucleus solitarius Outcome Participant Pathway interactions Pattern Phosphorylation Phosphotransferases Physiology Potassium Channel Process Proteins Regulation Role Series Signal Pathway Signal Transduction Signaling Molecule Site Stimulus Structural Models Structure System Testing Time Transcription Factor AP-1 abstracting base calmodulin-dependent protein kinase II chromatin immunoprecipitation combinatorial computerized data processing gene function inhibitor/antagonist insight mathematical model millisecond model development multi-scale modeling network models neuronal excitability neuroregulation promoter receptor research study response simulation transcription factor validation studies

项目摘要

DESCRIPTION (provided by applicant): Abstract Loss of homeostasis, defined as the dynamic maintenance of the internal environment within functionally tolerable limits, is understood as central to the initiation and progression of disease. The central objective of this proposal is to develop new insights into the mechanisms of homeostasis as it involves the brainstem nucleus tractus solitarius (NTS) and the role of the neuromodulator Angiotensin II (AngII) in hypertension. The NTS is a key integrative structure in the central neuronal orchestration of homeostasis, while AngII is one of the most pleiotropically active and therefore biomedically important molecules in mammalian biology. The NTS neuronal response to Ang II, acting through AT1R, involves processes that affect neuronal electrophysiology via the interplay of (1) membrane ion channels modulated via intracellular signaling, and (2) expression dynamics of multiple genes functioning in an interconnected network. Both of these contribute to the adaptive NTS response that contributes to the development and maintenance of changed homeostatic function in disease. The goal is for bridging from molecular level interaction networks to electrophysiological signal generation. The questions addressed here are fundamental for brain functioning and physiology; in particular, in connection to regulation of the response to various stimuli. To this end, we focus on the AT1R induced neuromodulation at two different temporal levels, in two Specific Aims. Aim 1, with focus on the AT1 receptor- to-signaling-to-electrophysiology, will develop a mathematical model of the rapid and transient modulation of membrane ion channel currents based on experimental data. This will support simulation study of the detailed interaction of signaling pathways and biophysical processes underlying short-to-intermediate timeframe adaptive electrophysiological activity patterns. Model predictions will be experimentally validated using pathway inhibitors and the results iteratively utilized in further model refinement. The focus of Aim 2 is to develop and experimentally validate a mathematical model of the regulatory network downstream of AT1R activation in NTS. To this end, we will follow a structured approach that we have previously developed to combine microarray gene expression data and promoter occupancy of key transcription factors. The network hypotheses will be experimentally validated using Chromatin ImmunoPrecipitation (ChIP)-based methods and the results will be used iteratively in further refinement of the regulatory network model. Successful completion of these Aims will provide the first systems level analysis of molecular mechanisms involved in the NTS adaptive response to AT1R activation, providing insights into the mechanisms of homeostasis. PUBLIC HEALTH RELEVANCE: Project Narrative Loss of homeostasis, defined as the dynamic maintenance of the internal environment within functionally tolerable limits, is understood as central to the initiation and progression of disease. The present project is based on the hypothesis that these processes arise from complex and dynamic neuronal processes that involve multiple signaling molecules and genes functioning over time in a hierarchical and interconnected network. We aim to combine computational models with experimental measurements in order to develop and validate hypotheses of the underlying molecular mechanisms.

描述（由申请人提供）：摘要体内平衡的丧失被定义为内部环境在功能可耐受范围内的动态维持，被认为是疾病发生和进展的核心。该提案的中心目标是对稳态机制产生新的见解，因为它涉及脑干孤束核 (NTS) 以及神经调节剂血管紧张素 II (AngII) 在高血压中的作用。 NTS 是中枢神经元稳态协调中的关键整合结构，而 AngII 是哺乳动物生物学中最具多效活性的分子之一，因此在生物医学上是重要的分子。 NTS 神经元对 Ang II 的反应通过 AT1R 起作用，涉及通过以下相互作用影响神经元电生理学的过程：(1) 通过细胞内信号传导调节的膜离子通道，以及 (2) 在互连网络中发挥作用的多个基因的表达动态。这两者都有助于适应性 NTS 反应，从而有助于疾病中改变的稳态功能的发展和维持。目标是连接分子水平相互作用网络和电生理信号生成。这里讨论的问题是大脑功能和生理学的基础问题；特别是与对各种刺激的反应的调节有关。为此，我们在两个具体目标中重点关注 AT1R 在两个不同时间水平诱导的神经调节。目标 1 重点关注 AT1 受体到信号传导到电生理学，将根据实验数据开发膜离子通道电流快速瞬态调制的数学模型。这将支持对信号通路和生物物理过程的详细相互作用的模拟研究，这些过程是中短期适应性电生理活动模式的基础。模型预测将使用途径抑制剂进行实验验证，并将结果迭代地用于进一步的模型细化。目标 2 的重点是开发并通过实验验证 NTS 中 AT1R 激活下游调控网络的数学模型。为此，我们将遵循我们之前开发的结构化方法，将微阵列基因表达数据和关键转录因子的启动子占据相结合。网络假设将使用基于染色质免疫沉淀 (ChIP) 的方法进行实验验证，结果将迭代用于进一步完善监管网络模型。这些目标的成功完成将为涉及 NTS 对 AT1R 激活的适应性反应的分子机制提供第一个系统级分析，从而提供对稳态机制的见解。公共健康相关性：项目叙述体内平衡的丧失被定义为在功能可承受的范围内动态维持内部环境，被认为是疾病发生和进展的核心。本项目基于这样的假设：这些过程源于复杂且动态的神经元过程，涉及多个信号分子和基因，随着时间的推移，在分层和互连的网络中发挥作用。我们的目标是将计算模型与实验测量相结合，以开发和验证潜在分子机制的假设。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

MicroRNA network changes in the brain stem underlie the development of hypertension.

脑干中的 MicroRNA 网络变化是高血压发生的基础。

DOI：
10.1152/physiolgenomics.00047.2015
发表时间：
2015-06-30
期刊：
Physiological genomics
影响因子：
4.6
作者：
Danielle DeCicco;Haisun Zhu;Anthony Brureau;J. Schwaber;R. Vadigepalli
通讯作者：
R. Vadigepalli

Multiscale model of dynamic neuromodulation integrating neuropeptide-induced signaling pathway activity with membrane electrophysiology.

将神经肽诱导的信号通路活性与膜电生理学相结合的动态神经调节的多尺度模型。

DOI：
发表时间：
2015-01-06
期刊：
影响因子：
3.4
作者：
Makadia, Hirenkumar K;Anderson, Warren D;Fey, Dirk;Sauter, Thomas;Schwaber, James S;Vadigepalli, Rajanikanth
通讯作者：
Vadigepalli, Rajanikanth

Intracellular Information Processing through Encoding and Decoding of Dynamic Signaling Features.

通过动态信号特征的编码和解码进行细胞内信息处理。