Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system that affects an estimated 350,000 Americans and over a million individuals worldwide. Since the pathogenesis of MS is not clear, no definitive treatment is as of yet available. Much of our current knowledge about contributing factors of MS is based on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Several theories for the pathogenesis of MS exist and implicate infiltrating T cells, pro-inflammatory cytokines, chemokines, activated microglia and astrocytes. Our research efforts in recent years on glia maturation factor (GMF), a protein isolated, sequenced and cloned in our laboratory, have demonstrated a major immunomodulatory function of GMF. Recently, we have established the GMF-dependent production of inflammatory cytokines/chemokines in microglia and the subsequent destruction of oligodendroglia (myelin producing cells) and neurons. Based on GMF's ability to activate microglia and induce several well- established pro-inflammatory mediators, we hypothesize that GMF is involved in the pathogenesis of MS/EAE. We have also provided strong experimental evidence using GMF-deficient mice, that an absence of endogenous GMF delays the onset and drastically reduces the severity of EAE, in both active and adaptive transfer models. Our results provided for the first time a novel rational for targeting GMF for therapeutic intervention in MS. The objective of this proposal is to study the effect of GMF inhibition in EAE and to elucidate GMF as a candidate for therapeutic intervention in MS. This proposal will investigate a novel therapeutic approach to effectively suppress GMF-function in EAE. Building on our recent success in suppressing GMF expression in vitro, we will use RNA interference (RNAi) to suppress GMF expression and an anti-GMF antibody to neutralize endogenous GMF protein in EAE mice. Our hypothesis is that the effective suppression of GMF-function will prove to be an effective strategy to slow, and perhaps reverse pathogenic processes in EAE. We will pursue two Specific Aims.
In Aim 1 A, we will study the ability of RNAi to suppress GMF expression in EAE mice and determine whether RNAi can prevent EAE.
In Aim 1 B, we will test whether the delivery of a neutralizing anti-GMF antibody to EAE mice will prevent or reverse pathological hallmarks of EAE.
In Aim 2, we will compare these two GMF-suppression strategies in the context of CNS inflammation.

Public Health Relevance

The lack of effective treatments for MS, a disabling chronic inflammatory demyelinating disease, represents a significant gap in the ability to treat this devastating disease. The aim of this proposal is to elucidate GMF, a well-established pro-inflammatory mediator, as a novel candidate for therapeutic intervention in MS/EAE. These studies may provide the scientific rationale for the development of a novel non-toxic therapy for MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Utz, Ursula
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University of Iowa
Schools of Medicine
Iowa City
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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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