Brain Ischemia and Nonlinear Dynamics

脑缺血和非线性动力学

基本信息

批准号：
8574746
负责人：
DONALD J DEGRACIA
金额：
$ 19.06万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574746
关键词：
Behavior Binding Biological Brain Brain Injuries Brain Ischemia Cells Cessation of life Clinical Clinical Research Clinical Trials Cluster Analysis Data Development Elements Equation Etiology Event Exploratory/Developmental Grant Failure Gene Expression Genes Genomics Healthcare Heart Arrest Hippocampus (Brain)Human Individual Injury Ischemia Ischemic Brain Injury Laboratory Study Life Light Link Logic Measures Methodology Microscopic Modeling Molecular Molecular Sequence Alteration Morbidity - disease rate Neurons Neuroprotective Agents Nonlinear Dynamics Ontology Outcome Output Pathway interactions Play Proteomics Published Comment Rattus Recommendation Recovery Reperfusion Injury Reperfusion Therapy Research Design Rest Secondary to Stroke Study models System Systems Biology Techniques Testing Therapeutic Time Work analytical method analytical tool biological adaptation to stress care burden cell injury cost high risk injured innovation mathematical model mathematical theory neuroprotection novel preclinical study protein aggregation public health relevance theories transcriptomics

项目摘要

DESCRIPTION (provided by applicant): Human brain ischemia and reperfusion (I/R) occurs clinically following stroke and cardiac arrest. Over 100 stroke and cardiac arrest clinical trials f neuroprotection have completely failed. This spectacular failure suggests there may be something fundamentally wrong with the current understanding of brain I/R. The current model of I/R injury, the "ischemic cascade", is a list of intracellular pathways induced in neurons by I/. We suggest that the failure of this viewpoint may rest in the assumption that a linear sequence of molecular changes causes outcome. We offer a novel, alternative, systems biology view of cell injury that posits all injury-induced changes in the cell contribute causally to outcome. Causality is not due to the action of linear pathways but to a nonlinear network of interactions. The theory is expressed by nonlinear ordinary differential equations. We seek to operationalize this theory by assessing means of measuring the differential equation variables. We propose the theory variables can be obtained from proteomic and transcriptomic data treated as quantitative deviations in the total amount of molecular damage and molecular stress responses from the control state. We propose to measure these distances in two classes of neurons, CA1 and CA3, using a well-studied model of global brain I/R in the rat.

描述（由申请人提供）：临床上，人脑缺血和再灌注（I/R）发生在中风和心脏骤停后。超过 100 项针对中风和心脏骤停的神经保护临床试验完全失败。这一惊人的失败表明，当前对大脑 I/R 的理解可能存在根本性错误。当前的 I/R 损伤模型，即“缺血级联”，是由 I/ 在神经元中诱导的一系列细胞内途径。我们认为，这种观点的失败可能在于分子变化的线性序列导致结果的假设。我们提供了一种新颖的、替代性的细胞损伤系统生物学观点，认为所有损伤引起的细胞变化都会对结果产生因果影响。因果关系不是由于线性路径的作用，而是由于非线性的相互作用网络。该理论用非线性常微分方程来表达。我们试图通过评估微分方程变量的测量方法来运用这一理论。我们提出理论变量可以从蛋白质组学和转录组学数据中获得，这些数据被视为分子损伤总量和分子应激反应与控制状态的定量偏差。我们建议使用经过充分研究的大鼠全脑 I/R 模型来测量两类神经元 CA1 和 CA3 中的这些距离。