Abstract Dr. L. Hensley
Title of Project Molecular Mechanisms Contributing to Gender Disparity in Multiple Sclerosis
Abstract Multiple sclerosis (MS) affects approximately 400,000 Americans, two-thirds of whom are female. It is a cruel disease that attacks individuals in the prime of their lives. The causes of MS remain elusive, but a myelin protein is likely to be the autoantigen responsible for initiating the inflammatory response in the CNS, and sex steroids may modulate the susceptibility to MS. Elucidation of the mechanisms by which these hormones influence microglial function and understanding how important myelin-specific proteins are regulated will be critical for understanding the basis for gender differences in MS. The long-term goals of this project are to determine the molecular mechanisms that result in a gender bias in MS. Aim 1 will use Western and Northern blot analyses to assess the effects of female sex steroids upon the regulation of microglia function by looking at expression levels of iNOS, a key enzyme in the production of inflammatory molecules. Since there are no steroid binding sites in the iNOS promoter, an alternative pathway by which these hormones may exert their effects will be investigated. In Aim 2, the effects of female sex steroids upon NFkB activity will be determined. Transient transfection of iNOS-luciferase constructs into microglial cells will be performed to examine NFkB activity in response to these hormones, as NFkB is a critical activator of iNOS gene expression. In Aim 3, the activity of specific kinases known to contribute to the regulation of the NFkB signalling cascade will also be examined. Modulation of the immune response by sex steroids is likely to contribute to the gender disparity of MS, but gender-specific expression of potential autoantigens in mediating susceptibility to the disease may also contribute. Therefore, in Aim 4, immunocytochemistry will be used to determine if the Plp protein, the most abundant protein found in mature CNS myelin, is expressed in the testes. Preliminary data demonstrate expression of the mRNA in Leydig cells, and expression of the protein could establish protective tolerance in males. These experiments should ultimately help lead to the design of better therapies and quality of life for people with MS.
Updated 10/31/2005
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