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

描述(申请人提供)：这项研究旨在确定血液中基因组和蛋白质组的变化，这些变化可能预测CpG ODN(未甲基化的胞嘧啶-鸟苷富含寡核苷酸)成功的预防性神经保护。这种方法包括通过激活Toll样受体(TLR)进行预适应，作为一种强有力的预防性治疗，用于缺血性脑损伤的高危患者。高危人群的预防性神经保护有可能保护患者免受毁灭性的神经并发症和死亡的影响。这项工作是基于缺血耐受的内源性神经保护现象，它为大脑抵御随后的缺血损伤提供了先决条件。TLRs是病原体相关分子(如细菌脂多糖、细菌DNA、单链RNA)的天然免疫受体家族。TLR9及其激动剂CpG ODns是一种新的神经保护候选药物，已在以啮齿动物为基础的缺血损伤模型中得到广泛验证。此外，CpG ODN在MAN的I/II/III期临床研究中显示出良好的安全性和耐受性。在一种新的猕猴皮质卒中模型中，从CpG诱导的神经保护研究中收集的RNA和血清样本将用于本提案中概述的基因组和蛋白质组研究。对血液中基因组和蛋白质组变化的分析可能有助于深入了解这些药物诱导神经保护的机制。此外，系统生物标记物的识别将为CpG ODN未来的临床试验提供关键信息，该临床试验将涉及有脑缺血风险的患者。

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.