Immune and Gilia Regulation of Pain & Analgesic Actions

免疫和吉利亚疼痛调节

• 批准号: 7498731
• 负责人: LINDA WATKINS
• 金额: $ 12.33万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498731
• 关键词: Absence of pain sensation; Acute; Address; Adverse effects; Affect; Agitation; Agonist; Ally; Alzheimer' s Disease; American; Analgesics; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Anus; Archives; Area; Astrocytes; Ataxia; Attenuated; Award; Basic Science; Behavior; Behavioral; Behavioral Model; Binding; Biological Assay; Blood - brain barrier anatomy; Brain; Brain region; CX3CL1 gene; Cell Nucleus; Cell Therapy; Cell Wall; Cells; Cerebrospinal Fluid; Cessation of life; Chemistry; Chronic; Clinical; Clinical Trials; Cluster Analysis; Code; Commit; Communities; Complementary DNA; Complex; Condition; Conditioned Culture Media; Confocal Microscopy; Constriction procedure; Custom; Cytokine Receptors; DNA; Data; Dependence; Dependovirus; Development; Diabetic Neuropathies; Dorsal; Dose; Drug Delivery Systems; Education; Elevation; Employee Strikes; Endotoxins; Ensure; Enzyme-Linked Immunosorbent Assay; Equipment; Event; Exhibits; Fever; Fibromyalgia; Food; Fractalkine; Funding; Future; Gene Activation; Gene Delivery; Gene Expression; Genes; Glial Fibrillary Acidic Protein; Goals; Grant; Green Fluorescent Proteins; HIV Envelope Protein gp120; HIV-1; Health; Heroin; Hospitals; Human; Hyperalgesia; IL10 gene; IL6 gene; Imines; Immune; Immune response; Immune system; Immunohistochemistry; In Vitro; Infection; Inflammation; Inflammatory; Infusion procedures; Injection of therapeutic agent; Injury; Interleukin-1; Interleukin-1 Receptors; Interleukin-10; Interleukin-4; Interleukins; Investigation; Ipsilateral; Label; Laboratories; Lateral; Lead; Legal; Link; Liquid substance; Literature; Location; Maintenance; Malignant Bone Neoplasm; Masks; Measures; Mechanics; Mediating; Mediation; Mediator of activation protein; Medical; Meningeal; Meninges; Mentorship; Messenger RNA; Methadone; Methamphetamine; Methods; Microglia; Migraine; Modeling; Monitor; Morphine; Mus; N-Methyl-D-Aspartate Receptors; Naloxone; National Institute of Drug Abuse; Necrosis; Nerve; Neuraxis; Neuroglia; Neurons; Neuropathy; Non-Viral Vector; Numbers; Operative Surgical Procedures; Opioid; Opioid Analgesics; Opioid Receptor; Orofacial Pain; Outcome; Oxycodone; Paclitaxel; Pain; Pain Research; Pain management; Pain-Free; Parkinson Disease; Pathology; Patients; Pattern; Peripheral; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phenotype; Pilot Projects; Plasma; Plasmids; Polyethylene Glycols; Positioning Attribute; Posterior Horn Cells; Preparation; Prevention; Principal Investigator; Procedures; Process; Production; Property; Proteins; Protocols documentation; Purpose; Radiculopathy; Rate; Rattus; Receptor Activation; Records; Recruitment Activity; Regulation; Rehabilitation therapy; Relative (related person); Reporter Genes; Reporting; Research; Research Design; Research Institute; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Rewards; Role; Sampling; Sciatic Neuropathy; Screening procedure; Sedation procedure; Senior Scientist Award; Sensory; Serotyping; Serum; Signal Transduction; Site; Solvents; Spinal; Spinal Anesthesia; Spinal Cord; Spinal Ganglia; Spinal cord injury; Spinal cord injury patients; Spinal cord posterior horn; Spinal nerve structure; Spreading Cortical Depression; Stimulus; Surface; Syndrome; System; Temporomandibular Joint; Testing; Therapeutic; Therapeutic Effect; Thermal Hyperalgesias; Time; Tissue Banks; Tissue Donations; Tissue Sample; Tissues; Touch sensation; Transgenes; Translating; Translations; Treatment Protocols; Trigeminal Nuclei; Trigeminal System; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; United States National Institutes of Health; Update; Upper arm; Variant; Ventilatory Depression; Viral; Virus; Water consumption; Withdrawal; Work; Writing; adeno-associated viral vector; allodynia; awake; base; behavior test; cell type; chemotherapy; chronic constriction injury; chronic pain; cisterna magna; clinical efficacy; clinically relevant; clinically significant; cytokine; day; design; drug discovery; drug of abuse; extracellular; follow-up; fractalkine receptor; gene function; gene therapy; human CX3CR1 protein; human TNF protein; immune function; improved; in vivo; inhibitor/antagonist; insight; interest; irritation; kappa opioid receptors; men; mimicry; morphine-3-glucuronide; morphine-6-glucuronide; nerve injury; neurochemistry; neutralizing antibody; novel; orofacial; painful neuropathy; plasmid DNA; pre-clinical research; preference; prevent; programs; promoter; receptor; relating to nervous system; research and development; research study; response; sciatic nerve; size; success; tissue fixing; transgene expression; transmission process; uptake; vector; vector-induced

DESCRIPTION (provided by applicant): The PI's preclinical research program seeks to understand how activation of peripheral immune cells and central nervous system glia (microglia and astrocytes) triggers a cascade of events leading to neuronal activation, pathological pain states, and dysregulation of the clinically relevant effects of analgesic drugs. The current research focus is directly relevant to her long-term goals of understanding (a) immune-neuralbidirectional interactions, and (b) pain modulation systems. The proposed project is a request for a K05 award for the PI to focus on programmatic investigations of pathological pain states. The currently funded projects include: (a) Immune/glial mediation of exaggerated pain states; NIDA K02 (Watkins PI; 6/03-5/08; DA015642); (b) Pain control via spinal interleukin-10 gene therapy; NIDA CEBRA Phase II (R01; Milligan PI; Watkins coPI; 09/04-09/09; DA018156); (c) Pain facilitation via neuron-to-glia signaling; NIDA R01 (Watkins PI; 3/05-12/09; DA017670); (d) Opioid analgesics: modulation.of trigeminal & Spinal glial activation; NIDCR R01 (Watkins PI; 7/06-4/11; DE017782); (e) Exploration of AV411, a blood brain barrier permeable glial activation inhibitor; Avigen (Watkins Pl;1/06-12/08); (f) Development of rat models to assess potential glial involvement in migraine; GlaxoSmithKline (Watkins PI; 1/07-12/09); (g) Translation from rats to humans: are chronic pain states in humans associated with glial activation in spinal cord and/or brain?; American Fibromyalgia Syndrome Association (Watkins CD Boulder PI; open ended small grant); (h) Human spinal cord glial cytokines & chronic pain NIAMSD R01 (Lorton, PI; Watkins, coPI; 7/07-6/12; AR054647); & (i) mRNA & protein analyses of spinal cord & CSF from spinal cord injury patients with vs. without chronic pain; Craig Spinal Cord Injury Treatment & Rehabilitation Hospital (Watkins CU Boulder PI; 9/07-open ended small grant). In addition, projects under review include: (j) Development of opioid therapeutic approaches that fail to activate glia; Covidien (Watkins PI); (k) Exploring the potential of glia for regulating clinically relevant opioid actions, R01 proposal (Watkins PI); and (I) Exploiting viral mimicry to develop new therapies for treating neuropathic pain, R21 Proposal (Leinwand PI; Watkins coPI). Thus this is an active & diverse research program exploring multiple levels of analyses at the forefront of pain research. All of these projects are focused on understanding immune/glial regulation of pain and analgesic actions. Beyond this extensive research program, the PI is committed to education of the scientific and lay communities on these topics via review articles and chapters and invited talks, and the mentorship of young investigators.

描述（由申请人提供）：PI 的临床前研究计划旨在了解外周免疫细胞和中枢神经系统胶质细胞（小胶质细胞和星形胶质细胞）的激活如何触发一系列事件，从而导致神经元激活、病理性疼痛状态和临床功能失调。镇痛药物的相关作用。目前的研究重点与她理解（a）免疫神经双向相互作用和（b）疼痛调节系统的长期目标直接相关。 拟议的项目是为 PI 申请 K05 奖项，以专注于病理疼痛状态的程序性研究。目前资助的项目包括： (a) 夸大疼痛状态的免疫/神经胶质调节； NIDA K02（沃特金斯 PI；6/03-5/08；DA015642）； (b) 通过脊髓白细胞介素 10 基因疗法控制疼痛； NIDA CEBRA II 期（R01；Milligan PI；Watkins coPI；09/04-09/09；DA018156）； (c) 通过神经元至神经胶质信号传导促进疼痛； NIDA R01（沃特金斯 PI；3/05-12/09；DA017670）； (d) 阿片类镇痛药：三叉神经和脊髓神经胶质激活的调节； NIDCR R01（沃特金斯 PI；7/06-4/11；DE017782）； (e) AV411（一种血脑屏障可渗透性神经胶质激活抑制剂）的探索； Avigen（沃特金斯广场；1/06-12/08）； (f) 开发大鼠模型以评估神经胶质细胞参与偏头痛的可能性；葛兰素史克（Watkins PI；1/07-12/09）； (g) 从大鼠到人类的转化：人类的慢性疼痛状态与脊髓和/或大脑中的神经胶质激活有关吗？；美国纤维肌痛综合症协会（Watkins CD Boulder PI；开放式小额资助）； (h)人脊髓神经胶质细胞因子和慢性疼痛NIAMSD R01(Lorton，PI；Watkins，coPI；7/07-6/12；AR054647)； (i) 患有和不患有慢性疼痛的脊髓损伤患者的脊髓和脑脊液的 mRNA 和蛋白质分析；克雷格脊髓损伤治疗与康复医院（沃特金斯大学博尔德分校 PI；9/07-开放式小额赠款）。此外，正在审查的项目包括： (j) 开发无法激活神经胶质细胞的阿片类药物治疗方法； Covidien（沃特金斯 PI）； (k) 探索神经胶质细胞调节临床相关阿片类药物作用的潜力，R01 提案（Watkins PI）； (I) 利用病毒拟态开发治疗神经性疼痛的新疗法，R21 提案（Leinwand PI；Watkins coPI）。因此，这是一个活跃且多样化的研究项目，探索疼痛研究前沿的多个层次的分析。 所有这些项目都专注于了解疼痛和镇痛作用的免疫/神经胶质调节。 除了这个广泛的研究项目之外，PI 还致力于通过评论文章和章节、邀请演讲以及对年轻研究人员的指导，对科学界和非专业界进行有关这些主题的教育。