Blood genomics and proteomics of CpG-induced neuroprotection in primate stroke.

描述（由申请人提供）： 本研究旨在确定血液中基因组和蛋白质组的变化，这可能是预测成功的预防性神经保护与CpG ODN（未甲基化的胞嘧啶-鸟苷丰富的寡脱氧核苷酸）。该方法涉及通过Toll样受体（TLR）激活进行预处理，作为缺血性脑损伤高风险患者的稳健预防性治疗。高危人群的预防性神经保护有可能保护患者免受破坏性神经系统并发症和死亡。这项工作是基于缺血耐受的内源性神经保护现象，其预先处理脑对随后的缺血损伤。TLR是病原体相关分子（例如细菌脂多糖、细菌DNA、单链RNA）的家族先天免疫受体。TLR 9及其激动剂CpG ODNs是一种新的神经保护治疗候选药物，已在啮齿动物缺血性损伤模型中得到广泛验证。此外，CpG ODNs在人类I/II/III期临床研究中显示出良好的安全性和耐受性。从恒河猴皮质卒中新模型中CpG诱导的神经保护研究中收集的RNA和血清样品将用于本提案中概述的基因组学和蛋白质组学研究。分析血液中的基因组和蛋白质组学变化可能会深入了解这些药物诱导神经保护的机制。此外，系统性生物标志物的鉴定将为未来涉及脑缺血风险患者的CpG ODN临床试验提供关键信息。 公共卫生相关性：本研究旨在确定血液中的变化，这可能是成功的预防性神经保护与CpG ODN（未甲基化的胞嘧啶-鸟苷丰富的寡脱氧核苷酸）的预测。分析血液中的基因组和蛋白质组学变化可能会深入了解这些药物诱导神经保护的机制。此外，系统性生物标志物的鉴定将为未来涉及脑缺血风险患者的CpG ODN临床试验提供关键信息。

DESCRIPTION (provided by applicant): This study is designed to identify changes in the blood, both genomic and proteomic, which may be predictive of successful prophylactic neuroprotection with CpG ODNs (unmethylated cytosine-guanosine rich oligodeoxynucleotides). This approach involves preconditioning through Toll-like receptor (TLR) activation as a robust prophylactic treatment for patients at high risk of ischemic brain injury. Prophylactic neuroprotection of high risk populations has the potential to protect patients from devastating neurological complications and death. This work is based on the endogenous neuroprotective phenomenon of ischemic tolerance, which preconditions the brain against subsequent ischemic injury. TLRs are a family innate immune receptors for pathogen-associated molecules (e.g. bacterial lipopolysaccharide, bacterial DNA, single stranded RNA). TLR9, and its agonist, CpG ODNs, is a new therapeutic candidate for neuroprotection that has been validated extensively in rodent-based models of ischemic injury. Additionally, CpG ODNs show good safety and tolerability in phase I/II/III clinical studies in man. RNA and serum samples collected from a study of CpG-induced neuroprotection in a novel model of cortical stroke in the rhesus macaque will be used for the genomic and proteomic studies outlined in this proposal. Analysis of genomic and proteomic changes in blood may lead insight into the mechanism by which these agents induce neuroprotection. Further, identification of systemic biomarkers would provide critical information for future clinical trial with CpG ODNs that would involve patients who are at risk of brain ischemia. PUBLIC HEALTH RELEVANCE: This study is designed to identify changes in the blood which may be predictive of successful prophylactic neuroprotection with CpG ODNs (unmethylated cytosine-guanosine rich oligodeoxynucleotides). Analysis of genomic and proteomic changes in blood may lead insight into the mechanism by which these agents induce neuroprotection. Further, identification of systemic biomarkers would provide critical information for future clinical trial with CpG ODNs that would involve patients who are at risk of brain ischemia.