Multiscale Model of the Vagal Outflow to the Heart
迷走神经流出心脏的多尺度模型
基本信息
- 批准号:9152617
- 负责人:
- 金额:$ 57.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-10 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAnatomyArrhythmiaAutomobile DrivingBehaviorBiological AssayBiological Neural NetworksBrain StemCardiacCardiac OutputCardiac healthCerealsClinical DataColorComputer SimulationCoronary arteryDataDiseaseEarly DiagnosisElectrophysiology (science)Experimental ModelsFemaleFunctional disorderFuzzy LogicGangliaGenerationsGenesGenetic TranscriptionGoalsHealthHeartHeart DiseasesHeart RateHeart failureIndividualIschemiaKnowledgeLabelLeft ventricular structureLigationLinkMaintenanceMeasuresModalityModelingMolecularMyocardial IschemiaNeuronal PlasticityNeuronsNitric OxidePalliative CarePathogenesisPathologyPhenotypePhysiologicalPreventionRattusRegulator GenesRosaSinoatrial NodeSourceStudy modelsSudden DeathSystemTestingTropismVagus nerve structureVentricularViral Vectoranatomical tracingbasechronotropicdorsal motor nucleusexperimental studyheart functionhemodynamicsimprovedinsightinterestlaser capture microdissectionmalemodel developmentmulti-scale modelingmultimodalitynetwork modelsneuronal excitabilitynovelnovel therapeuticsnucleus ambiguusprotective effectresponsetranscriptomics
项目摘要
PROJECT SUMMARY
Vagal control of the heart has seen renewed interest due to the now well-recognized potential of manipulating
cardiac vagal activity for novel therapeutic opportunities in treating heart disease. Recent anatomical and
physiological evidence shows that vagal cardiac control is multimodal at both pre- and post-ganglionic
neuronal levels. Coordination between multiple modes of control (e.g., of heart rate, ventricular contractility,
etc) is essential for heart health. Disruption of such coordination is a hallmark of heart failure and arrhythmias,
for example. Studies thus far have largely focused on the physiological effects of the vagus on heart rate
without delving into the underlying neural networks, where insights are likely to yield targets for fine-grained
manipulation of vagal activity to treat heart disease. Our project is aimed at addressing this unmet need by
focusing on the central neuronal as well as cardiac ganglionic circuits driving chrono-, dromo- and iono-
tropism. We will pursue an integrated multiscale modeling strategy that combines fine-grained anatomical
tracing of control circuits and high-throughput transcriptional analysis of single neurons identified based on
circuit connectivity, with computational modeling of the multiscale closed loop vagal cardiac control. These
involve hemodynamics, brainstem neuronal networks, and cardiac ganglionic circuits involved in the
coordinated inotropic and chronotropic control of the heart. We will develop detailed electrophysiological
models of neuronal excitability in nucleus ambiguus (NA) and dorsal motor nucleus (DMV), as well as the
targeted cardiac ganglia, and incorporate the transcriptional changes identified from coronary artery ligation
experiments in these models. We hypothesize that coordination and integration of the control of rate and
contractility occurring at the level of the NA/DMV and the level of the cardiac ganglia are the basis for
cardioprotective vagal cardiac outflows. We will test this hypothesis in three Aims: (1) Develop a multiscale
network model framework integrating the key modules controlling SA node and left ventricle. (2) Determine the
molecular mechanisms affecting the coordination involved in cardiac functional control in heart disease by
linking gene regulatory networks and neural network behavior. (3) Test model predictions in selective
manipulation of function experiments. Our multiscale computational modeling framework will enable us to
combine and interpret the anatomical, transcriptional, and physiological results from experiments. Our
investigative team has previously collaborated in modeling the baroreflexes and comprises complementary
expertise in all aspects of the proposal. Our approach is expected to identify the relative contribution of
brainstem circuits and cardiac ganglionic circuits to the coordination of multimodal vagal control. Our expected
results, by uncovering the molecular and physiological mechanisms underlying the source and maintenance of
coordinated vagal outflows, have significant implications for identifying targets for early diagnosis, prevention,
and even novel palliative therapy in treating heart disease.
项目摘要
由于现在众所周知的操纵潜力,对心脏的迷走神经控制已经引起了人们的兴趣
心脏迷走神经活性,用于治疗心脏病的新型治疗机会。最近的解剖学和
生理证据表明,迷走神经心脏控制是多模式的
神经元水平。多种控制模式之间的协调(例如,心率,心室收缩力,
等)对于心脏健康至关重要。这种协调的破坏是心力衰竭和心律不齐的标志,
例如。迄今为止的研究主要集中在迷走神经的生理影响上
没有深入研究潜在的神经网络,在这种神经网络中,洞察力可能会产生细粒度的目标
操纵迷走神经活动以治疗心脏病。我们的项目旨在满足这种未满足的需求
专注于中央神经元以及心脏神经节电路,驱动计时,dromo-和iono-
向性。我们将采用一个集成的多尺度建模策略,该策略结合了细粒度的解剖学
跟踪对照电路和基于基于的单个神经元的高通量转录分析
电路连通性,具有多尺度闭环迷走神经控制的计算建模。这些
涉及血液动力学,脑干神经元网络和心脏神经节电路
对心脏的肌育肌力和表年度控制。我们将开发详细的电生理学
神经元兴奋性模型(NA)和背运动核(DMV)以及
靶向心脏神经节,并结合了冠状动脉连接确定的转录变化
这些模型中的实验。我们假设对利率控制的协调和整合
发生在NA/DMV水平和心脏神经节水平的收缩率是
心脏保护迷走神经外流。我们将以三个目的测试这一假设:(1)开发多尺度
网络模型框架集成了控制SA节点和左心室的密钥模块。 (2)确定
通过
连接基因调节网络和神经网络行为。 (3)选择性的测试模型预测
操作功能实验。我们的多尺度计算建模框架将使我们能够
结合并解释实验的解剖学,转录和生理结果。我们的
调查团队以前曾合作过建模降压力,并包括补充
提案的各个方面的专业知识。我们的方法有望确定
脑干电路和心脏神经节电路多模式迷走神经控制。我们的期望
结果,通过发现源和维护的基础的分子和生理机制
协调的迷走神流出,对确定早期诊断,预防,预防,
甚至在治疗心脏病方面的新型姑息治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES SCHWABER其他文献
JAMES SCHWABER的其他文献
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{{ truncateString('JAMES SCHWABER', 18)}}的其他基金
Molecular Neurogenetics of the Brainstem Neuronal Source of Cardioprotective Vagal Outflow
心脏保护性迷走神经流出脑干神经源的分子神经遗传学
- 批准号:
10522387 - 财政年份:2022
- 资助金额:
$ 57.96万 - 项目类别:
Molecular Neurogenetics of the Brainstem Neuronal Source of Cardioprotective Vagal Outflow
心脏保护性迷走神经流出脑干神经源的分子神经遗传学
- 批准号:
10641909 - 财政年份:2022
- 资助金额:
$ 57.96万 - 项目类别:
Multiscale Model of the Vagal Outflow to the Heart
迷走神经流出心脏的多尺度模型
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9908155 - 财政年份:2017
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Neuroimmune Cell Networks in Opioid Dependence and Withdrawal
阿片类药物依赖和戒断中的神经免疫细胞网络
- 批准号:
8676771 - 财政年份:2013
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Neuroimmune Cell Networks in Opioid Dependence and Withdrawal
阿片类药物依赖和戒断中的神经免疫细胞网络
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8600490 - 财政年份:2013
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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
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8502346 - 财政年份:2012
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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
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8372524 - 财政年份:2012
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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
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8843930 - 财政年份:2012
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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
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新型低成本、高通量 DNA 测序平台
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