Treatment of Demyelinating Disease with HSP90 Inhibitors

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DESCRIPTION (provided by applicant): The demyelinating autoimmune disease experimental autoimmune encephalomyelitis (EAE) is an often-used animal model to study possible causes and therapeutic interventions for Multiple Sclerosis (MS), which involves T-cell activation, migration into the CMS, induction of parenchymal cell inflammatory gene expression, damage to oligodendrocytes and myelin loss, and eventually irreversible axonal damage. One of the key signaling events required for inflammatory gene expression is activation of transcription factors, such as NFkB in glial cells and T cells, and of other such as transcription factor NFAT in T cells. Anti-inflammatory agents which reduce transcription factor activation could therefore be of therapeutic benefit. We and others have shown that induction of a heat shock response (HSR) potently reduced activation of transcription factor NFkB and inflammatory gene expression in brain glial cells, and that a brief period of hyperthermia (42¿C for 20 minutes) completed prevented the onset and development of EAE in mice. A HSR can also be induced by inhibiting activity of the HSP90 protein. Inhibition of HSP90 has two primary consequences: release of transcription factor HSF1 which in turn activates the HSR; and release and degradation of 'client' proteins, some of which can potentiate inflammatory responses or increase survival of inflammatory cells, such as the protein kinase AKT. In the current proposal, we will characterize the efficacy of novel small molecular weight HSP90 inhibitors to reduce glial (astrocyte and microglial) and T-cell activation, and to reduce clinical and pathological progression in EAE, with the ultimate goal of identifying compounds for further testing in MS patients. This goal will be addressed in 3 specific aims: Aim 1, characterizing the ability and mechanism of HSP90 inhibitors to block glial cell inflammation; Aim 2, determine the efficacy and mechanisms of HSP90 inhibitors to block T-cell activation; Aim 3, use selected HSP90 inhibitors to block clinical and histological symptoms in chronic and relapsing EAE model .