Immune /Glial Mediation of Exaggerated Pain States

夸大疼痛状态的免疫/神经胶质调节

• 批准号: 6555010
• 负责人: LINDA WATKINS
• 金额: $ 12万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6555010
• 关键词: AIDS; HIV envelope protein gp120; RNase protection assay; antigen antibody reaction; astrocytes; behavior test; cell cell interaction; disease /disorder model; glia; hyperalgesia; immunoregulation; in situ hybridization; inflammation; interleukin 1; interleukin 6; laboratory rat; microglia; neuritis; neurons; pain; postdoctoral investigator; sciatic nerve; spine; training; tumor necrosis factor alpha; zymosan

DESCRIPTION (provided by applicant): The PI's preclinical research program seeks to understand how activation of peripheral immune cells and central nervous system microglia and astrocytes triggers a cascade of events leading to neuronal activation and pathological pain states. This current research focus is directly relevant to her long-term goals of understanding (a) immune-neural interactions and (b) endogenous pain modulation systems. The proposed project is a request for a K02 award for the PI to develop skills now required by new results in programmatic investigations of pathological pain states. The 2 animal models employed induce clinically relevant exaggerated pain states by: (a) peri-spinal administration of HIV-1 gp 120 and (b) sciatic inflammatory neuropathy. Extensive evidence indicates that peripheral immune cells and spinal immune-like glial cells play critical roles in the creation and maintenance of exaggerated pain phenomena. Of the substances released by these cells upon activation, the strongest evidence to date points to the proinflammatory cytokines tumor necrosis factor, interleukin-1, and interleukin-6. These signaling molecules are key spinal mediators of pathological pain induced by both peri-spinal gp120 and sciatic inflammatory neuropathy. Their release from peri-sciatic immune cells is also correlated with the induction and intensity of sciatic inflammatory neuropathy. The two parent R01 grants are aimed at clarifying the immune/glial mechanisms underlying these pain models using immunological, anatomical, molecular, pharmacological, and behavioral approaches. The PI seeks to gain further training in molecular biology techniques (RNase Protection Assays, in situ hybridization, and adenoviral vectors for gene therapy), to enroll in responsible conduct of research coursework, and to continue her education through project-relevant coursework and research forums. Additionally, the released time will foster further professional growth by yielding coherent blocks of time for concentrating on research and review projects.

描述（由申请人提供）： PI 的临床前研究项目旨在了解外周免疫细胞和中枢神经系统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和病理性疼痛状态。目前的研究重点与她理解（a）免疫神经相互作用和（b）内源性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 K02 奖项，以培养病理疼痛状态的程序性研究新结果现在所需的技能。所采用的 2 种动物模型通过以下方式诱导临床相关的夸大疼痛状态：(a) 脊髓周围施用 HIV-1 gp 120 和 (b) 坐骨炎性神经病。大量证据表明，外周免疫细胞和脊髓免疫样胶质细胞在过度疼痛现象的产生和维持中发挥着关键作用。在这些细胞激活后释放的物质中，迄今为止最有力的证据表明促炎细胞因子肿瘤坏死因子、白细胞介素 1 和白细胞介素 6。这些信号分子是脊髓周围 gp120 和坐骨炎性神经病诱导的病理性疼痛的关键脊髓介质。它们从坐骨周围免疫细胞的释放也与坐骨炎性神经病的诱导和强度相关。两项母公司 R01 资助旨在利用免疫学、解剖学、分子、药理学和行为方法阐明这些疼痛模型背后的免疫/神经胶质机制。 PI 寻求获得分子生物学技术（RNase 保护测定、原位杂交和用于基因治疗的腺病毒载体）方面的进一步培训，报名参加负责任的研究课程，并通过项目相关课程和研究论坛继续接受教育。此外，腾出的时间将通过集中时间集中于研究和审查项目来促进进一步的专业发展。