Brain Ischemia and Nonlinear Dynamics

描述（由申请人提供）：临床上发生脑缺血和再灌注（I/R）后，中风和心脏骤停。超过100例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，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，“缺血级联”，是由I/R在神经元中诱导的细胞内途径的列表。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。我们提供了一个新的，替代的，系统生物学的细胞损伤的观点，假定所有损伤引起的细胞变化的因果关系的结果。因果关系不是由于线性路径的作用，而是由于相互作用的非线性网络。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。我们提出的理论变量可以从蛋白质组学和转录组学数据处理作为定量偏差的总量的分子损伤和分子应激反应从控制状态。我们建议测量这些距离在两个类的神经元，CA 1和CA 3，使用一个良好的研究模型的全球脑I/R在大鼠。

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.