Multiple sclerosis is an inflammatory demyelinating disease of the human central nervous system. The primary cause or causes of MS are unknown. The purpose of this proposal is to obtain a better understanding of the mechanisms of inflammation and myelin and oligodendrocyte destruction in MS lesions by analyzing tissue from MS patients. The underlying hypothesis of this proposal is that inflammation and breakdown of the blood-brain barrier activate parenchymal microglia cells. These activated microglia cells then attack and destroy myelin and oligodendrocyte. The proposal is divided into three Specific Aims. The first Specific Aim will collect, process and characterize tissue from multiple sclerosis, other neurological diseases, and control brains. MS lesions will be identified and the extent of demyelination, remyelination, microglia and astrocyte activation, regions of blood-brain barrier breakdown, and extent of inflammation will be determined. The second Specific Aim will investigate the role of activated microglia in myelin and oligodendrocyte destruction. We will determine the three-dimensional relationship between activated microglia and myelin internodes and oligodendrocytes in MS brains. Preliminary studies indicate that microglia attack and destroy normal appearing myelin and that a select population of VCAM-1-positive microglia/monocytes attack oligodendrocytes. An important question raised by these studies is the mechanism by which microglia become activated in MS brain. This questions will be addressed by studies in Specific Aim 3, which investigate mechanisms of leukocyte trafficking in MS lesions. Leukocyte extravasation into tissue occurs by a series of interactions between the Beta2 integrins on leukocytes and the Ig-like molecules on endothelial cells. We will determine if the Beta2 integrins (LFA-1, MAC-1, P150-95, (Beta2alphad) and their punitive receptors (ICAM-1, ICAM-2, ICAM-3, ICAM-4, PECAM, VCAM-1) are induced or upregulated in MS lesions. Studies in Specific Aim 3 will also determine the distribution of the Beta1 integrin, VLA-4 and its receptor, the CS1 form of fibronectin. VLA-4 is expressed by leukocytes and is thought to play an essential role in their entry into active demyelinating lesions in MS brain. VLA-4 is a current therapeutic target in MS patients. We anticipate that these studies will identify adhesion molecules that are induced or upregulated in MS lesions. If it can be demonstrated that these molecules play an essential role in leukocyte trafficking, they become attractive targets for therapeutic intervention in MS.
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