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

CpG 诱导的灵长类中风神经保护的血液基因组学和蛋白质组学。

• 批准号: 8450126
• 负责人: Rebecca Lynn Williams
• 金额: $ 4.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450126
• 关键词: Agonist; Animals; Bacterial DNA; Biological Markers; Blood; Brain; Brain Ischemia; Cell Maturation; Cessation of life; Clinical Research; Clinical Trials; Cytosine; Family; Future; Gene Chips; Gene Expression Regulation; Genes; Genomics; Guanosine; Immunologic Receptors; Injection of therapeutic agent; Injury; Interleukin-12; Investigation; Ischemic Brain Injury; Lead; Leukocytes; Link; Lipopolysaccharides; Liquid Chromatography; Macaca mulatta; Measurement; Modeling; Mus; NK Cell Activation; Natural Killer Cells; Neurologic; Patients; Phase; Population; Primates; Prophylactic treatment; Proteomics; RNA; Receptor Activation; Regulation; Resolution; Risk; Rodent; Safety; Sampling; Serum; Stroke; Toll-like receptors; Work; base; cytokine; design; high risk; insight; man; mouse model; neuroprotection; nonhuman primate; novel; novel therapeutics; pathogen; preconditioning; prognostic; prophylactic; research study; response; tandem mass spectrometry; two-dimensional

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.

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学的变化，这些变化可能预测CpG ODNs（未甲基化的胞嘧啶-鸟苷富寡脱氧核苷酸）成功的预防性神经保护。这种方法包括通过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一种强有力的预防性治疗。高危人群的预防性神经保护有可能保护患者免受毁灭性的神经系统并发症和死亡。这项工作是基于内源性的缺血耐受的神经保护现象，这是大脑对随后的缺血性损伤的先决条件。tlr是一类病原体相关分子（如细菌脂多糖、细菌DNA、单链RNA）的先天免疫受体。TLR9及其激动剂CpG ODNs是一种新的神经保护治疗候选药物，已在基于啮齿动物的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。从一项研究中收集的RNA和血清样本将用于本提案中概述的基因组和蛋白质组学研究，该研究收集了一种新的恒河猴皮质中风模型中cpg诱导的神经保护。对血液中基因组和蛋白质组学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，系统生物标志物的鉴定将为未来涉及脑缺血风险患者的CpG ODNs临床试验提供关键信息。