DEVELOPMENT OF TOLL-LIKE RECEPTOR AGONISTS AS NEUROPROTECTANTS IN BRAIN ISCHEMIA

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 Toll样受体（TLR）信号传导可以将对中风的炎症（损伤）反应重新编程为大脑中的神经保护反应。TLR 9和7的激动剂（CpG ODN和咪喹莫特 IMQ）是用于预防性神经保护对抗中风的先导化合物。从啮齿动物到人类的临床转化失败促使进行额外的临床前评价。使用灵长类动物中风模型，我们的目的是建立基本的疗效和药代动力学数据。我们的初步研究支持开发用于高危中风患者的神经保护策略，以通过以下方式在非人灵长类动物中进行进一步测试：目的1。确定在NHP皮质卒中模型中使用TLR 9（K和D混合CpG ODN）和TLR 7（IMQ）候选药物作为预防性治疗以实现神经保护功效的最佳剂量。目标2.在雄性NHP卒中模型中确定最佳药物的神经保护功效的时间窗。目标3.确定老年NHP预防性治疗的神经保护效果。目标4。确定在NHP模型中重复皮质卒中的神经保护功效。目标5。确定最佳药物作为女性NHP预防性卒中治疗的神经保护功效。目标6。确定药代动力学和毒性特征。目标7。根据疗效、药代动力学和毒性，提交IND申请，选择最佳候选药物。进度：目标1研究接近完成，尽管盲法研究设计虽然是最佳的，但阻止了对迄今收集的数据进行任何初步分析。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Toll-Like Receptor (TLR) signaling can reprogram an inflammatory (injurious) response to stroke into a neuroprotective response in the brain. Agonists of TLRs 9 and 7 (CpG ODNs and imiquimod IMQ, respectively) are lead compounds for prophylactic neuroprotection against stroke. Clinical translational failures from rodent to human prompted additional preclinical evaluation. Using a primate stroke model we aim to establish essential effacy and pharmacokinetic data. Our preliminary studies support development of neuroprotective strategies for high-risk stroke patients to be further tested in the non-human primate via: Aim 1. Determine the optimal dose to achieve neuroprotective efficacy with TLR9 (K-and D-mix CpG ODNs) and TLR7 (IMQ) candidate drugs as prophylactic therapy in a NHP model of cortical stroke. Aim 2. Determine the time window of neuroprotective efficacy for the optimal drug in male NHP stroke model. Aim 3. Determine neuroprotective efficacy as prophylactic therapy in aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal drug as prophylactic stroke therapy in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles. Aim 7. Submit an IND application for the optimal candidate based on efficacy, pharmacokinetics and toxicity. Progress: Aim 1 studies are near completion, although the blinded study design, while optimal, prevents any preliminary analysis of the data collected so far.