Immune /Glial Mediation of Exaggerated Pain States

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、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了解(A)免疫-神经相互作用和(B)内源性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K02奖，以发展目前病理性疼痛状态程序性研究的新结果所需的技能。所使用的两种动物模型通过：(A)脊髓周围注射HIV-1GP 120和(B)坐骨神经炎性神经病来诱导临床相关的夸大疼痛状态。广泛的证据表明，外周免疫细胞和脊髓免疫样神经胶质细胞在夸大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指向促炎症细胞因子肿瘤坏死因子、白介素1和白介素6。这些信号分子是脊髓周围gp120和坐骨神经炎性神经病引起的病理性疼痛的关键脊髓介质。它们从坐骨神经周围免疫细胞中的释放也与坐骨神经炎性神经病的诱导和强度有关。Parent R01的两项赠款旨在通过免疫学、解剖学、分子、药理学和行为学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(核糖核酸酶保护分析、原位杂交和用于基因治疗的腺病毒载体)的进一步培训，参加负责任的研究课程，并通过与项目相关的课程和研究论坛继续她的教育。此外，所释放的时间将通过产生连贯的时间块来专注于研究和审查项目，从而促进进一步的专业发展。

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.