Autoimmune encephalomyelitis and Bcl-2- interacting mediator

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is an animal model for human multiple sclerosis (MS). Although the etiological factors that trigger the disease vary, the final pathological outcome of MS and EAE is the destruction of myelin-producing oligodendrocytes and their associated neuronal axons by inflammatory cells. While the morphological characteristics of dying oligodendrocytes and inflammatory cells are well documented, the cellular and molecular mechanisms of cell death in MS and EAE are not clear. Recent studies from several laboratories including ours indicate that apoptosis, or programmed cell death, plays an essential role in the pathogenesis of the disease. Thus, mice deficient in genes that mediate apoptosis are resistant to EAE, and selective manipulation of apoptosis is effective for the treatment of the disease. Apoptosis can be mediated by at least two distinct pathways: the mitochondria! pathway, which is controlled by members of the B cell leukemia (Bcl)-2 family and the death receptor pathway, which is initiated by the members of the tumor necrosis factor family. This proposal is inspired by our recent discovery that Bim (Bcl-2-interacting mediator), a key initiator of the mitochondrial pathway of apoptosis, plays essential roles in EAE. Mice deficient in Bim are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG), and have a selective defect in their anti-MOG T cell responses. The goal of this proposal is to elucidate the cellular and molecular mechanisms of Bim action in autoimmune encephalomyelitis. We hypothesize that Bim mediates the death of lymphoid and myeloid cells as well as oligodendrocytes in EAE through a mechanism that involves Bax, and that the Bim-Bax axis of the mitochondrial pathway of apoptosis (the Bim pathway) plays a dual role in EAE (i.e., it can both promote and inhibit the disease depending on its target of actions). These theories will be tested in animal models of multiple sclerosis at molecular, cellular and organismal levels under the following specific aims. Specific Aim 1: To test the hypothesis that Bim and Bax expressed by the immune system and the nervous system play different roles in EAE. Specific Aim 2: To test the hypothesis that Bim and Bax dictate the fates of myelin-specific T cells in EAE. Specific Aim 3: To test the hypothesis that Bim mediates the death of oligodendrocytes through Bax. Information generated from these studies will not only help advance our understanding of the mechanisms of Bim and Bax actions in models of multiple sclerosis but also aid in the development of apoptosis-based strategies for the treatment of the disease.