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导致神经元激活和病理性疼痛状态的级联事件。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。拟议项目是为PI申请K 02奖，以开发病理性疼痛状态程序研究新结果所需的技能。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）脊髓周围给予HIV-1 gp 120和（B）坐骨神经炎性神经病。大量证据表明，外周免疫细胞和脊髓免疫样胶质细胞在产生和维持夸张的疼痛现象中起着关键作用。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。这些信号分子是由脊髓周围gp 120和坐骨神经炎性神经病变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的释放也与坐骨神经炎性神经病变的诱导和强度相关。两个R 01赠款旨在使用免疫学、解剖学、分子学、药理学和行为学方法阐明这些疼痛模型的免疫/神经胶质机制。 PI寻求获得分子生物学技术（RNA酶保护试验，原位杂交和基因治疗的腺病毒载体）的进一步培训，报名参加负责任的研究课程，并通过项目相关的课程和研究论坛继续她的教育。此外，释放的时间将通过产生连贯的时间块来集中于研究和审查项目，从而促进进一步的专业成长。

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.