Thrombin mediated cytotoxicity during cerebral ischemia

基于文献和我们自己的试验数据，我们提出了一个新颖而令人兴奋的假设， 神经元损伤通过凝血酶及其受体PAR-1刺激星形胶质细胞活化， 所产生的星形胶质细胞对损伤的反应产生神经元的可传递的旁分泌保护。 神经元、星形胶质细胞、内皮细胞、周细胞和少突胶质细胞共同构成了神经系统。 神经血管单位或NVU。从几个目标中产生的数据将有助于了解 预处理的良好记录现象的机制;将提供相当大的 深入了解脑损伤的不同脆弱性机制，并可能产生 中风患者的治疗选择。为了实现这些目标，我们正在创造新的条件， 基因敲除小鼠将为更广泛的研究领域提供研究工具。前一 裁决，R 01 NS 075930，涵盖2011年8月15日至2015年3月31日，涉及4个目标。所有拟议 工作已经完成并发表或正在审查中。我们之前的裁决数据 已经通过两项临床试验对中风护理产生了重大影响。但我们的 先前的数据不能完全解释NVU的元件之间的已知差异， 特别是星形胶质细胞和内皮细胞比神经元更能耐受缺血。是什么 凝血酶介导的预处理机制，我们能把这个机制与 其他形式的预适应和围适应为什么大脑含有凝血酶原mRNA， 蛋白质和什么目的可以通过凝血酶激活大脑？我们能否推导出 了解大脑对损伤的反应，特别是探索细胞亚型 损伤期间星形胶质细胞、神经元、周细胞、少突胶质细胞和内皮细胞之间的相互作用 细胞？为了回答这些问题，并解决本奖项的中心假设， 应用程序，我们添加了重要的新模型，我们的剧目，并产生试点数据 谈到拟议的新的具体目标的可行性和新奇。

We propose a novel and exciting hypothesis—based on literature and our own pilot data—that neuronal injury stimulates astrocyte activation via thrombin and its receptor PAR-1, and the resulting astrocyte response to injury yields transmissible paracrine protection of neurons. Together, neurons, astroctyes, endothelial cells, pericytes, and oligodendroglia comprise the neurovascular unit, or NVU. Data generated from the several aims will yield insights into the mechanism for the well-documented phenomenon of pre-conditioning; will provide considerable insights into the mechanisms of differential vulnerability to cerebral injury; and would likely yield treatment options for stroke patients. To accomplish the aims, we are creating novel conditional knock-out mice that will provide research tools to the broader research field. The previous award, R01 NS075930, covered 8/15/2011 to 03/31/2015 and involved 4 aims. All proposed work has been completed and published or under review. The data from our prior award has already influenced stroke care significantly, in the form of two funded clinical trials. However, our prior data could not fully explain the known differences among the elements of the NVU, specifically, that astrocytes and endothelial cells tolerate ischemia better than neurons. What is the mechanism of thrombin-mediated pre-conditioning, and can we relate that mechanism to other forms of pre- and peri-conditioning? Why does the brain contain prothrombin mRNA and protein and what purpose could be served by thrombin activation in brain? Could we derive insights about the response of the brain to injury, and specifically explore the cell-subtype interactions during injury among astrocytes, neurons, pericytes, oligodendroglia, and endothelial cells? To answer these questions, and to address the central hypothesis of the present award application, we added significant new models to our repertoire, and generated pilot data speaking to the feasibility and novelty of the proposed new specific aims.