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.
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