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.

我们提出了一个新颖而令人兴奋的假设 - 基于文学和我们自己的飞行员数据神经元损伤可通过凝血酶及其受体PAR-1刺激星形胶质细胞激活，并且导致星形胶质细胞对损伤的反应可导致神经元的可传播旁分泌保护。神经元，天体，内皮细胞，周细胞和少突胶质细胞包括神经血管单元或NVU。从几个目标产生的数据将产生对有据可查的预先条件现象的机制；将提供考虑深入了解脑损伤差异脆弱性的机制；并可能产生中风患者的治疗选择。为了实现目标，我们正在创建新颖的条件淘汰小鼠将为更广泛的研究领域提供研究工具。上一个奖励，R01 NS075930，涵盖8/15/2011至03/31/2015，并参与了4个目标。都提出了工作已完成，发布或正在审查。我们先前奖励的数据已有已经以两项基本临床试验的形式对中风护理产生了重大影响。但是，我们的先前的数据无法完全解释NVU元素之间的已知差异，具体而言，星形胶质细胞和内皮细胞比神经元更好地耐缺血。是什么凝血酶介导的预处理的机制，我们可以将这种机制与其他形式的前和周期性？为什么大脑含有蛋白mRNA和蛋白质，通过大脑中的凝血酶激活能够提供什么目的？我们可以得出吗？关于大脑对损伤的反应的见解，并专门探索细胞提取物星形胶质细胞，神经元，周细胞，少突齿和内皮的损伤中的相互作用细胞？回答这些问题，并解决本奖奖的中心假设应用程序，我们在曲目中添加了重要的新模型，并生成了试点数据谈到拟议的新特定目标的可行性和新颖性。