Immune and Gilia Regulation of Pain & Analgesic Actions

描述(申请人提供)：PI的临床前研究计划试图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，导致神经元激活、病理性疼痛状态和止痛药临床相关效果的失调。目前的研究重点与她了解(A)免疫-神经双向相互作用和(B)疼痛调制系统的长期目标直接相关。 拟议的项目是为PI申请K05奖，以专注于病理性疼痛状态的程序性研究。目前获得资助的项目包括：(A)夸大疼痛状态的免疫/神经胶质调节；NIDA K02(Watkins PI；6/03-5/08；DA015642)；(B)通过脊髓白介素10基因疗法控制疼痛；NIDA CEBRA第二阶段(R01；Milligan Pi；Watkins Copi；09/04-09/09；DA018156)；(C)通过神经元到神经胶质信号促进疼痛；NIDA R01(Watkins PI；3/05-12/09；DA017670)；(D)阿片类止痛药：三叉神经和脊髓神经胶质激活的调节；NIDR01(Watkins PI；(7/06-4/11；DE017782)；(E)探索血脑屏障渗透性胶质细胞激活抑制剂AV411；Avigen(Watkins Pl；1/06-12/08)；(F)建立大鼠模型以评估偏头痛潜在的神经胶质参与；葛兰素史克(Watkins Pi；1/07-12/09)；(G)从大鼠到人的翻译：人类的慢性疼痛状态是否与脊髓和/或脑中的胶质细胞激活有关？；美国纤维肌痛综合征协会(Watkins CD Boulder PI；开放式小额赠款)；(H)人类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)有慢性疼痛的脊髓损伤患者与无慢性疼痛的脊髓损伤患者的脊髓和CSF的mRNA和蛋白质分析；Craig脊髓损伤治疗和康复医院(Watkins CU Boulder Pi；9/07-不限名额小额赠款)。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(Watkins Pi)；(K)探索胶质细胞调节临床相关阿片类药物活动的潜力，R01建议(Watkins Pi)；(I)利用病毒拟态开发治疗神经病理性疼痛的新疗法，R21建议(Leinwand Pi；Watkins Copi)。因此，这是一个积极和多样化的研究计划，探索疼痛研究前沿的多个层次的分析。所有这些项目都集中在了解免疫/神经胶质对疼痛和止痛作用的调节。除了这一广泛的研究计划外，PI还致力于通过评论文章和章节、特邀演讲以及年轻研究人员的指导，在这些主题上对科学和非专业社区进行教育。

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.