The long-term objective of this competitive renewal is to evaluate the functional role of chemokine and chemokine receptors in contributing to neurologic disease and repair following infection with a neurotropic murine coronavirus, mouse hepatitis virus (MHV). Infection of susceptible mice with MHV reproducibly results in an acute encephalomyelitis followed by a chronic demyelinating disease characterized clinically by ascending hind-limb paralysis and histologically by mononuclear cell infiltration into the central nervous system (CNS) accompanied by white matter destruction. Due to the similarities in clinical and histologic disease between MHV-induced demyelination and the human demyelinating disease multiple sclerosis (MS), the MHV system is considered an excellent model in which to study the underlying pathological mechanisms contributing to human demyelinating diseases such as MS. Similar to MS, both T cells and macrophages are thought to be important in contributing to white matter destruction. In addition, chemokine and chemokine receptors are expressed within the CNS of MS patients as well as MHV- infected mice indicating a prominent role in the pathogenesis of disease. Indeed, during the previous funding periods (initiated in 2000), we have defined functional roles for chemokines and chemokine receptors in regulating neuroinflammation that is involved in both host defense and demyelination in response to MHV infection by regulating lymphocyte and macrophage infiltration. The present proposal builds upon our previous work and offers the opportunity to define the functional role of chemokines and chemokine receptors in i) protecting oligodendrocytes (the myelin-producing cell of the CNS) from damage/death and ii) regulating the biology of engrafted neural progenitor cells e.g. positional migration and proliferation which contributes to axonal remyelination. Together, these studies will extend our current understanding of how chemokines and their receptors participate in protection and repair. Further, the data obtained from these experiments will identify potentially novel therapeutic approaches for treatment of MS as well as other human demyelinating diseases.

Public Health Relevance

The long-term goals of this research proposal are to use a viral model of the human demyelinating disease, multiple sclerosis (MS) to better understand how resident cells of the brain protect themselves from damage/death during ongoing disease as well as to define approaches to promote repair. It is our long-term goal to develop novel interventional treatments for limiting the severity of disease symptoms in MS patients as well as other human demyelinating diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041249-11
Application #
8214533
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2001-04-01
Project End
2015-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
11
Fiscal Year
2012
Total Cost
$321,113
Indirect Cost
$102,363
Name
University of California Irvine
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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Marro, Brett S; Grist, Jonathan J; Lane, Thomas E (2016) Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination. J Immunol 196:1855-64
Grist, Jonathan J; Marro, Brett; Lane, Thomas E (2016) Neutrophils and viral-induced neurologic disease. Clin Immunol :
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Herz, Josephine; Sabellek, Pascal; Lane, Thomas E et al. (2015) Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice. Stroke 46:2916-25
Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F et al. (2014) Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies. Expert Rev Neurother 14:1169-79
Blanc, Caroline A; Rosen, Hugh; Lane, Thomas E (2014) FTY720 (fingolimod) modulates the severity of viral-induced encephalomyelitis and demyelination. J Neuroinflammation 11:138
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Weinger, Jason G; Marro, Brett S; Hosking, Martin P et al. (2013) The chemokine receptor CXCR2 and coronavirus-induced neurologic disease. Virology 435:110-7
Villegas-Mendez, Ana; Gwyer Findlay, Emily; de Souza, J Brian et al. (2013) WSX-1 signalling inhibits CD4⁺ T cell migration to the liver during malaria infection by repressing chemokine-independent pathways. PLoS One 8:e78486

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