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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：
THOMAS E DICK
金额：
$ 61.32万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10002328
关键词：
Affect Bayesian Modeling Bilateral Biological Biological Markers Bioperiodicity Blood Brain Stem Breathing Cause of Death Cell Nucleus Clinical Coagulation Process Computer Models Coupling Critical Illness Data Data Analyses Dependence Diagnosis Early Diagnosis Early identification Endotoxemia Escherichia coli Fibrin Frequencies Functional disorder Goals Heart Rate Homeostasis Human Implant Individual Infection Inflammation Inflammation Mediators Inflammatory Inflammatory Response Intensive Care Units Interleukin-1 beta Life Link Measures Medical Microinjections Modeling Multiple Organ Failure Nerve Neural Network Simulation Neurons Neurophysiology - biologic function Observational Study Organ Pathologic Pathway Analysis Patients Pattern Peripheral Physiological Pontine structure Pressoreceptors Prognostic Marker Public Health Pulse Pressure Rattus Regulation Research Personnel Respiration Risk Role Sepsis Septic Shock Septicemia Severity of illness Sinus Arrhythmia Systemic Inflammatory Response Syndrome Systemic infection Testing Therapeutic Intervention Time Tissues Translating Visceral analytical tool base cytokine experimental study gram-negative sepsis heart rate variability indexing mortality risk network dysfunction neural network neuroinflammation neuromechanism neurophysiology neuroregulation nucleus ambiguus outcome forecast prevent prospective relating to nervous system respiratory sensory feedback septic septic patients therapeutic cytokines therapeutic target

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：
JOURNAL OF PHYSIOLOGY-LONDON
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：
Neuroscience
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：
EXPERIMENTAL NEUROLOGY
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.