Modeling Brainstem Inflammation's Role in Systemic Dysfunction during Sepsis

模拟脑干炎症在脓毒症期间全身功能障碍中的作用

基本信息

  • 批准号:
    10002328
  • 负责人:
  • 金额:
    $ 61.32万
  • 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:
    2017-09-18 至 2022-05-31
  • 项目状态:
    已结题

项目摘要

Sepsis is systemic infection accompanied by an uncontrolled inflammatory response; a condition that can deteriorate rapidly. Early diagnosis is critical for survival. Heart rate variability (HRV), a proposed biomarker for sepsis, predicts its prognosis but is too nonspecific to make a diagnosis. Often HRV is quantified by its power spectra, its variability in the frequency domain; the `high-frequency' component reflects respiratory modulation of vagal nerve activity. Computational deterministic models of the brainstem cardiorespiratory control networks have proposed plausible neural mechanisms for the vago-respiratory coupling. In contrast to HRV, Dynamic Network Analysis (DyNA) and Dynamic Bayesian Network (DyBN) models are highly specific and successful in identifying a `tipping point' in sepsis, i.e. when a controlled inflammatory response becomes uncontrolled but its many variables are hard to measure. Recently, we identified that the brainstem becomes inflamed in endotoxemia. We hypothesize that progressive inflammation is a critical factor in losing HRV, ventilatory pattern variability (VPV), and cardiorespiratory coupling (CRC) associated with sepsis. We propose to build on the strengths of agent-based and computational modeling approaches and perform model-driven experiments to determine how alterations of brainstem neurophysiology in sepsis limit physiologic pattern variability. Our preliminary data show that endotoxemic rats lose CRC progressively in association with proinflammatory cytokines expression first in the nucleus tractus solitarius (nTS) then in the nucleus Ambiguus. Further, consistent with a progressive loss of CRC focal IL-1β microinjections in the nTS uncouples the arterial pulse pressure's influence on respiration leaving RSA intact. The Specific Aims are: 1) to develop DyNa and DyBN models of cytokine expression in brainstem cardiorespiratory control nuclei during septicemia to determine if central and peripheral inflammation patterns, 2) to adapt these models to critically-ill humans at risk for sepsis and probe the robustness of the model by applying therapeutic interventions in rats, and 3) to apply our control model to propose plausible and testable mechanisms for the effects of cytokines on the function of cardiorespiratory control circuitry. Our computational model of the neural control of cardiorespiratory coupling as well as the models defining the interactions among cytokines in tissue inflammation have been applied successfully to other conditions (sympatho-respiratory coupling) or to peripheral tissues (cytokine expression and interaction). Integrating these models will provide cross-scale mechanistic explanations for the loss of RSA and CVC observed during sepsis, identify critical cytokines for therapeutic intervention, and will establish a scientific rationale for using CRC and variability measures as complementary and sensitive biomarkers of sepsis.
败血症是全身性感染,伴有不受控制的炎症反应;这种情况可以

项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Advancing respiratory-cardiovascular physiology with the working heart-brainstem preparation over 25 years.
  • DOI:
    10.1113/jp281953
  • 发表时间:
    2022-05
  • 期刊:
  • 影响因子:
    5.5
  • 作者:
    Paton, Julian F. R.;Machado, Benedito H.;Moraes, Davi J. A.;Zoccal, Daniel B.;Abdala, Ana P.;Smith, Jeffrey C.;Antunes, Vagner R.;Murphy, David;Dutschmann, Mathias;Dhingra, Rishi R.;McAllen, Robin;Pickering, Anthony E.;Wilson, Richard J. A.;Day, Trevor A.;Barioni, Nicole O.;Allen, Andrew M.;Menuet, Clement;Donnelly, Joseph;Felippe, Igor;St-John, Walter M.
  • 通讯作者:
    St-John, Walter M.
Pre- and post-inspiratory neurons change their firing properties in female rats exposed to chronic intermittent hypoxia.
暴露于慢性间歇性缺氧的雌性大鼠中,吸气前和吸气后神经元的放电特性发生变化。
  • DOI:
    10.1016/j.neuroscience.2019.03.043
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    3.3
  • 作者:
    Souza,GeorgeMPR;Barnett,WilliamH;Amorim,MateusR;Lima-Silveira,Ludmila;Moraes,DaviJA;Molkov,YaroslavI;Machado,BeneditoH
  • 通讯作者:
    Machado,BeneditoH
Chemoreception and neuroplasticity in respiratory circuits.
  • DOI:
    10.1016/j.expneurol.2016.05.036
  • 发表时间:
    2017-01
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Barnett, William H.;Abdala, Ana P.;Paton, Julian F. R.;Rybak, Ilya A.;Zoccal, Daniel B.;Molkov, Yaroslav I.
  • 通讯作者:
    Molkov, Yaroslav I.
Inhibitory control of active expiration by the Bötzinger complex in rats.
  • DOI:
    10.1113/jp280243
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Flor KC;Barnett WH;Karlen-Amarante M;Molkov YI;Zoccal DB
  • 通讯作者:
    Zoccal DB
Divergent COVID-19 Disease Trajectories Predicted by a DAMP-Centered Immune Network Model.
  • DOI:
    10.3389/fimmu.2021.754127
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    7.3
  • 作者:
    Day JD;Park S;Ranard BL;Singh H;Chow CC;Vodovotz Y
  • 通讯作者:
    Vodovotz Y
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THOMAS E DICK其他文献

THOMAS E DICK的其他文献

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{{ truncateString('THOMAS E DICK', 18)}}的其他基金

Modeling Brainstem Inflammation's Role in Systemic Dysfunction during Sepsis
模拟脑干炎症在脓毒症期间全身功能障碍中的作用
  • 批准号:
    9282192
  • 财政年份:
    2017
  • 资助金额:
    $ 61.32万
  • 项目类别:
Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
  • 批准号:
    7500412
  • 财政年份:
    2008
  • 资助金额:
    $ 61.32万
  • 项目类别:
Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
  • 批准号:
    7884487
  • 财政年份:
    2008
  • 资助金额:
    $ 61.32万
  • 项目类别:
Modeling of Pathogenic Breathing Pattern Dysregulation in Cardiopulmonary Disease
心肺疾病致病性呼吸模式失调的建模
  • 批准号:
    7687923
  • 财政年份:
    2008
  • 资助金额:
    $ 61.32万
  • 项目类别:
Cardiorespiratory Afferent Control in Heart Failure
心力衰竭的心肺传入控制
  • 批准号:
    7031632
  • 财政年份:
    2005
  • 资助金额:
    $ 61.32万
  • 项目类别:
Cardiorespiratory Afferent Control in Heart Failure
心力衰竭的心肺传入控制
  • 批准号:
    7388833
  • 财政年份:
    2005
  • 资助金额:
    $ 61.32万
  • 项目类别:
Cardiorespiratory Afferent Control in Heart Failure
心力衰竭的心肺传入控制
  • 批准号:
    6908685
  • 财政年份:
    2005
  • 资助金额:
    $ 61.32万
  • 项目类别:
Cardiorespiratory Afferent Control in Heart Failure
心力衰竭的心肺传入控制
  • 批准号:
    7214176
  • 财政年份:
    2005
  • 资助金额:
    $ 61.32万
  • 项目类别:
Sympathetic activation by intermittent hypoxia
间歇性缺氧激活交感神经
  • 批准号:
    6564829
  • 财政年份:
    2002
  • 资助金额:
    $ 61.32万
  • 项目类别:
VENTROLATERAL PONS SHAPES THE RESPONSE TO HYPOXIA
脑桥腹外侧决定缺氧反应
  • 批准号:
    6338857
  • 财政年份:
    2000
  • 资助金额:
    $ 61.32万
  • 项目类别:

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用于高维疾病绘图和边界检测的贝叶斯建模和推理”
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