Multiple sclerosis (MS) is a chronic human demyelinating disorder of the central nervous system (CNS). The identification of a wide range of inflammatory molecules (pro-inflammatory cytokines, cell adhesion molecules, inducible nitric oxide synthase and peroxynitrite) in brain lesions of patients with MS and rats/mice with experimental allergic encephalomyelitis (EAE), an animal model of MS, suggests that a broad spectrum of inflammatory processes plays the crucial role in the pathogenesis of MS/EAE. Therefore, analysis of molecular mechanisms for the regulation of these inflammatory molecules in activated glial cells and in the CNS of animals with EAE should decipher the said mechanisms of the disease process in MS/EAE and further the possibility of developing effective therapies for MS patients with drugs that block the activation of inflammatory molecules. Activation of NF-kB, a pro-inflammatory transcription factor, is important for the induction of inflammatory molecules. The investigators have found that NF-kB is induced in the neural tissues of rats and mice with EAE. However, the role of this induced activation of NF-kB is not known. Therefore, Specific Aim I has been designed to delineate the role of NF-kB activation in the disease process of EAE. The investigators have found that activation of p21ras by the expression of a dominant-negative mutant of p21ras inhibits the activation of NF-kB in activated glial cells suggesting that p21ras may regulate the in vivo activation of NF-kB in the CNS of EAE animals and the disease process of EAE. Therefore, Specific Aim II will examine the effects of inhibitors of p21ras on the disease process of EAE. Since cAMP-dependent proteinase kinase (PKA) differentially regulates the activation of NF-kB in astrocytes and macrophages, Specific Aim III has been devoted to investigate the molecular basis for the differential regulation of NF-kB activation in two different cell types (astrocytes and macrophages) by PKA. The proposed studies are significant and will utilize the state of the art methodologies in cellular and molecular biology to enhance our understanding of the signaling pathways for the activation of NF-kB in vitro in glial cells and in vivo in the spinal cord of EAE and to provide promising therapeutic strategies for MS patients.
Showing the most recent 10 out of 55 publications
