Thrombin mediated cytotoxicity during cerebral ischemia

脑缺血期间凝血酶介导的细胞毒性

基本信息

批准号：
9927678
负责人：
Patrick D Lyden
金额：
$ 11.02万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2020-09-12
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927678
关键词：
Address Agonist Animals Argatroban Astrocytes Attention Award Biological Assay Brain Caring Cell Communication Cells Cerebral Ischemia Cerebrum Clinical Trials Collaborations Data Dose Elements Endothelial Cells F2R gene Factor Xa Funding Genes Injury Ischemia Knockout Mice Lentivirus Vector Literature Mass Spectrum Analysis Mediating Messenger RNA Microfluidics Modeling Monitor Mus Neuronal Injury Neurons Oligodendroglia PAR-1 Receptor Peptide Hydrolases Peptides Pericytes Phase Play Process Property Proteins Proteomics Prothrombin Publishing Reaction Research Research Personnel Role Signal Transduction Stimulus Stroke Tamoxifen Techniques Testing Thrombin Trypsin Work base behavioral outcome brain cell conditional knockout conditioning cytotoxicity experimental study improved in vivo inhibitor/antagonist innovation insight neuroprotection neurovascular unit novel paracrine preconditioning receptor response response to brain injury response to injury stroke patient tool

项目摘要

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.

我们根据文献和我们自己的试验数据提出了一个新颖且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，由此产生的星形胶质细胞对损伤的反应产生了神经元的可传递的旁分泌保护。神经元、星形细胞、内皮细胞、周细胞和少突胶质细胞共同构成神经血管单元（NVU）从几个目标生成的数据将产生对神经血管单元的深入了解。有据可查的预调节现象的机制将提供相当大的帮助；深入了解不同的脑损伤脆弱性机制；并可能产生成果为了实现这些目标，我们正在创造新的有条件的治疗方案。基因敲除小鼠将为更广泛的研究领域提供研究工具。奖项，R01 NS075930，涵盖 2011 年 8 月 15 日至 2015 年 3 月 31 日，涉及 4 个目标。工作已完成并发布或正在审查我们先前获奖的数据。中风已经以两项资助的临床试验的形式显着影响了护理。先前的数据无法完全解释 NVU 要素之间的已知差异，具体来说，星形胶质细胞和内皮细胞比神经元更能耐受缺血。凝血酶介导的预处理机制，我们能否将该机制与其他形式的预调节和围调节为什么大脑中含有凝血酶原 mRNA 和蛋白质以及大脑中凝血酶激活可以起到什么作用？关于大脑对损伤的反应的见解，并特别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？回答这些问题，并解决本奖项的中心假设应用程序中，我们在我们的库中添加了重要的新模型，并生成了试点数据谈到所提出的新具体目标的可行性和新颖性。