NINDS Cooperative Program in Translational Research

NINDS 转化研究合作项目

• 批准号: 7942710
• 负责人: MARY P STENZEL-POORE
• 金额: $ 126.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942710
• 关键词: Acute; Adjuvant; Agonist; Animal Model; Anti-Inflammatory Agents; Aspirin; Blood Platelets; Brain; Brain Ischemia; Cell Death; Cessation of life; Clinical; Clinical Investigator; Clinical Trials; Clinical Trials Design; Contracts; Coronary Artery Bypass; Cytosine; Data; Development; Dose; Drug Formulations; Drug Kinetics; Evaluation; Event; Exclusion Criteria; FDA approved; Failure; Family; Female; Future; Goals; Guanosine; Histopathology; Hour; Human; Imiquimod; Impaired cognition; In Vitro; Individual; Infarction; Inflammatory; Injury; Intellectual Property; International; Ischemia; Ischemic Brain Injury; Lead; Licensing; Lipopolysaccharides; Macaca mulatta; Magnetic Resonance Imaging; Measurement; Modeling; Monitor; Morbidity - disease rate; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Neuroprotective Agents; Oregon; Pamphlets; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Primates; Prophylactic treatment; RNA; Receptor Activation; Receptor Signaling; Recurrence; Research Ethics Committees; Research Institute; Research Personnel; Rodent; Rodent Model; Safety; Scientist; Secure; Services; Signal Pathway; Signal Transduction; Stroke; TLR7 gene; TLR9 gene; Testing; Therapeutic; Therapeutic Index; Therapeutic Intervention; Time; Toll-like receptors; Toxic effect; Toxicology; Transient Ischemic Attack; Translating; Translational Research; United States National Institutes of Health; Vaccine Therapy; Viral; Work; aged; attenuation; base; cell injury; drug candidate; drug testing; high risk; in vivo; industry partner; motor deficit; neuroprotection; nonhuman primate; novel; novel strategies; novel therapeutics; pathogen; post stroke; pre-clinical; preclinical evaluation; preclinical study; preconditioning; programs; prophylactic; receptor; research and development; research clinical testing; response; small molecule; success

(precondition) its response to acute ischemia from that of induced cell injury signaling cascades to induction of neuroprotective pathways (tolerance). Such endogenous neuroprotection occurs through Toll Like Receptor (TLR) signaling which reprograms an inflammatory (injurious) response to stroke into an antiinflammatory (neuroprotective) response. We offer the preferred agonists (CpG ODNs and imiquimod - IMQ) of TLR 9 and 7 respectively as lead compounds for prophylactic neuroprotection against stroke. Although robust rodent data have been produced, past and recent translational failures require additional preclinical evaluation. Accordingly, we have developed a new primate stroke model for assessment of putative pharmacotherapeutics and propose to perform rigorous trials of our recently discovered neuroprotectants to establish essential effacy and pharmacokinetic data. Thus our preliminary studies support new robust 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 for 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 K- and D-mix CpG ODNs and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 3. Determine neuroprotective efficacy CpG ODN (K and D mix) and IMQ as prophylactic therapy in a model of cortical stroke in the aged NHP. Aim 4. Determine the neuroprotective efficacy of repeated administration of CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a NHP model of cortical stroke. Aim 5. Determine the neuroprotective efficacy of the optimal CpG ODN (K- and D-mix) and IMQ as prophylactic therapy in a model of cortical stroke in female NHPs. Aim 6. Determine pharmacokinetic and toxicity profiles of CpG ODN (K- and D-mix) and IMQ as potential stroke therapeutics. Aim 7. Submit an IND application for the optimal TLR candidate based on efficacy, pharmacokinetics and toxicity profiles.

（前提条件）其对急性缺血的反应从诱导细胞损伤信号级联到诱导