Brain Ischemia and Nonlinear Dynamics

描述（由申请人提供）：人脑缺血再灌注（I/R）在中风和心脏骤停后临床发生。超过100个中风和心脏骤停的神经保护临床试验完全失败了。这一惊人的失败表明，目前对大脑I/R的理解可能存在根本性的错误。目前的I/R损伤模型，即“缺血级联”，是由I/R在神经元中诱导的一系列细胞内通路。我们认为，这种观点的失败可能在于假设分子变化的线性序列导致结果。我们提供了一种新颖的、可选的、系统生物学的细胞损伤观点，假设所有损伤引起的细胞变化都对结果有因果关系。因果关系不是由于线性途径的作用，而是由于相互作用的非线性网络。该理论用非线性常微分方程表示。我们试图通过评估测量微分方程变量的方法来实现这一理论。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。我们建议在两类神经元（CA1和CA3）中测量这些距离，使用一个研究得很好的大鼠大脑全局I/R模型。

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.