The goal of our research is to understand the mechanisms of demyelination mediated by cytotoxic proteins generated during inflammation and immunological reactions. The prototypes of these cytotoxic factors belong to either rapidly-acting channel formers such as C5b-9 and perforin, or slow-acting cytokines such as tumor necrosis factor (TNF), lymphotoxin, and IL-1. We demonstrated one function of C5b-9 as an effector to stimulate hydrolysis of myelin basic protein in myelin, and to mobilize LTB4 in oligodendrocytes (OLG). Recently, we explored the role of TNF in demyelination. Astrocytes stimulated by Newcastle disease virus (NDV) or endotoxin produce TNF that kills OLG. TNF also demyelinates rodent explants, and is detected in astrocytes within active multiple sclerosis lesions. Thus, virus-induced cytokines can participate in demyelination by both killing OLG and inducing immunopathological processes. In this proposal, we will investigate; 1. The regulation of virus-mediated TNF production, especially the signal messenger pathway to induce TNT synthesis. 2. The mechanisms of TNF mRNA stabilization. 3. The effect of sublytic TNF on the synthesis of myelin proteins in OLG. 4. Production of complement proteins by astrocytes and its regulation by cytokines and viruses. Primary rat astrocytes and NDV will be used as the respective target and the stimulus and cytokines derived from activated astrocytes such as the TNF will be used to stimulate rat OLG and astrocytes in Projects 0005 and 0007. Studies of signal pathways include assays for PKC activity and diacylglycerol generation. Tyrosine kinase involvement will be addressed by examining virus-induced phosphorylaiton of PLC immunoprecipitates. Virus-induced TNF gene activation will be studies by nuclear run-on, the mRNA stability by northern. In addition, various promotor-TNF CDNA constructs will be used to identify the stability conferring sequences in transient transfection system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Specialized Center (P50)
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University of Maryland Baltimore
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