Elucidation of the molecular mechanisms that regulate inflammation in the central nervous system (CNS) is critical to our understanding of a broad spectrum of diseases, including multiple sclerosis, Alzheimer's, and Parkinson's. These diseases are responsible for significant morbidity and mortality, and new prevention and treatment approaches are urgently needed. This proposal builds on our recent finding that glia maturation factor (GMF), a highly conserved protein unique to the brain, serves as an important immune modulator by promoting the production and secretion of pro-inflammatory cytokines leading to the activation of microglia, the antigen presenting cells in the brain. The Human Genome Sequence Consortium has identified the gene of GMF in chromosome 14. In this proposal, we will study experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis, with the hypothesis that GMF contributes to the pathogenesis of EAE. This research will include investigations on the already available GMF knockout mice, wild type mice, and GMF transgenic mice (in the final stages of development) in which GMF transgene will be reintroduced in GMF knockout mice under the influence of astrocyte-specific GFAP promoter. This will provide, for the first time, a unique opportunity to study the pathogenesis of EAE in the contrasting settings of no GMF, normal amount of GMF, and high expression of GMF.
AIM I : To study the effects of GMF on the two major signal transduction cascades involved in CNS inflammation and immune processes, namely, the p38 MAP kinase and JAK/STAT pathways. We will utilize cultured brain cells, astrocytes, microglia and oligodendroglia, derived from GMF knockout versus wild type mice.
AIM II : To study the role of GMF in the pathophysiology of EAE and to establish that the absence of GMF mitigates the severity of the disease. (A) GMF knockout and wild type mice will be challenged with the proper antigen to induce EAE. The development and the histopathology of the brain and spinal cord at various stages of the disease will be compared. (B) To evaluate the expression profiles of cytokines and the free radical generating mediators during the progression of EAE in the brain, spinal cord and in isolated mononuclear cells. Knowledge obtained from this study can also be applied to degenerative diseases of the brain where microglial activation plays an important role, such as Alzheimer's and Parkinson's. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047145-04
Application #
7238669
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
2004-07-01
Project End
2009-01-14
Budget Start
2007-05-01
Budget End
2009-01-14
Support Year
4
Fiscal Year
2007
Total Cost
$323,419
Indirect Cost
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Zaheer, Smita; Thangavel, Ramasamy; Wu, Yanghong et al. (2013) Enhanced expression of glia maturation factor correlates with glial activation in the brain of triple transgenic Alzheimer's disease mice. Neurochem Res 38:218-25
Zaheer, Smita; Wu, Yanghong; Yang, Xi et al. (2012) Efficient down-regulation of glia maturation factor expression in mouse brain and spinal cord. Neurochem Res 37:1578-83
Zaheer, Smita; Wu, Yanghong; Yang, Xi et al. (2012) Clinical course of myelin oligodendrocyte glycoprotein 35-55 induced experimental autoimmune encephalomyelitis is aggravated by glia maturation factor. Neurochem Int 60:215-9
Thangavel, R; Stolmeier, D; Yang, X et al. (2012) Expression of glia maturation factor in neuropathological lesions of Alzheimer's disease. Neuropathol Appl Neurobiol 38:572-81
Zaheer, S; Thangavel, R; Sahu, S K et al. (2011) Augmented expression of glia maturation factor in Alzheimer's disease. Neuroscience 194:227-33
Zaheer, Smita; Wu, Yanghong; Sahu, Shailendra K et al. (2011) Suppression of neuro inflammation in experimental autoimmune encephalomyelitis by glia maturation factor antibody. Brain Res 1373:230-9
Zaheer, Smita; Wu, Yanghong; Sahu, Shailendra K et al. (2010) Overexpression of glia maturation factor reinstates susceptibility to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in glia maturation factor deficient mice. Neurobiol Dis 40:593-8
Thangavel, R; Sahu, S K; Van Hoesen, G W et al. (2009) Loss of nonphosphorylated neurofilament immunoreactivity in temporal cortical areas in Alzheimer's disease. Neuroscience 160:427-33
Thangavel, Ramasamy; Van Hoesen, Gary W; Zaheer, Asgar (2009) The abnormally phosphorylated tau lesion of early Alzheimer's disease. Neurochem Res 34:118-23
Thangavel, R; Van Hoesen, G W; Zaheer, A (2008) Posterior parahippocampal gyrus pathology in Alzheimer's disease. Neuroscience 154:667-76

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