The underlying mechanisms involved in the pathogenesis of the human demyelinating disease multiple sclerosis (MS) are not well understood. Available evidence indicates that the cause of MS is multifactorial and includes both the genetic background of the host as well as environmental influences. Infection of susceptible strains of mice with the coronavirus mouse hepatitis virus (MHV), a positive-stranded RNA virus, leads to a chronic, progressive, demyelinating disease with many clinical and histologic similarities with MS. Animals often develop partial to complete hind-limb paralysis. Although viral RNA persists in the CNS, the host immune response is thought to be the key factor in contributing to demyelination. T-lymphocytes and macrophages are associated with demyelinating plaque lesions in both MS patients as well as MHV-infected mice. The long range goal of this research proposal is to define the cellular mechanisms mediating demyelination in MHV-infected mice. First, emphasis will be placed on the role of the CD4+ T lymphocytes. These cells appear to be crucial in participating in the demyelinating process most likely by release of soluble factors which activate both inflammatory macrophages and resident glia to release cytotoxic factors. A second goal of this project is to study the signals i.e. chemokines which function in attracting CD4+ T cells as well as macrophages to the CNS to sites of viral persistence. Finally, this proposal will analyze the contributions of cytotoxic factors tumor necrosis factor alpha (TNF-a) and nitric oxide (NO) in MHV-induced demyelination. Together, these studies will provide insight into the complex immunological mechanisms involved in CNS demyelinating disease and allow a better understanding of the pathological mechanisms which exist in human demyelinating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS037336-04
Application #
6151547
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1998-02-01
Project End
2003-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
4
Fiscal Year
2000
Total Cost
$105,307
Indirect Cost
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Liu, M T; Keirstead, H S; Lane, T E (2001) Neutralization of the chemokine CXCL10 reduces inflammatory cell invasion and demyelination and improves neurological function in a viral model of multiple sclerosis. J Immunol 167:4091-7

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