CNS CYTOKINES AND THEIR IMPACT ON IMMUNE-MEDIATED DEMYELINATION

  • Dhib-Jalbut, Suhayl (PI)
  • JOHNSON, KENNETH (PI)
  • SHIN, MOON (PI)
  • KOSKI, CAROL LEE (PI)
  • Vanguri, Padmavathy (PI)
  • BISWALL, NILAMBAR (PI)
  • COLE, GERALD (PI)
  • CARRIGAN, DONALD (PI)
  • SHIN, MOON (PI)
  • KOSKI, CAROL LEE (PI)
  • Vanguri, Padmavathy (PI)

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/013/31/98

ASJC

  • Clinical Neurology
  • Neurology
  • Molecular Biology
  • Oncology
  • Cancer Research
  • Virology
  • Cell Biology
  • Immunology