Exploring biomarkers of sex-based disparities in relapsing multiple sclerosis

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Project Summary Multiple Sclerosis (MS) affects approximately one million people in the United States and is the leading cause of disability in young adults,1 but little is known about its etiology and underlying pathology.2,3 MS is approximately three times more common in females than males, and evidence suggests that this ratio is increasing worldwide.1-3 Although males are less susceptible, they tend to have more severe forms of the disease, and are more likely to accumulate significant disability as a result.1-3 Evidence suggests that the environment and sex hormones can cause molecular changes that alter the expression of MS-associated genes, which may explain these sex-based disease desparities.1,2,6-12 We hypothesize that gene expression alterations contribute to the sex differences in MS. Therefore, the goal of this application is to compare the transcriptome and miRNA profiles of males and females with relapsing MS using the following two specific aims. Aim 1: Identify and compare the actively expressed mRNAs in the transcriptome of males and females with relapsing-remitting MS and healthy controls. For this aim we will conduct a non-experimental, discovery-based omics study that will isolate and analyze the transcriptomes from blood samples collected from MS patients using RNA-seq. Aim 2: Analyze the miRNA profiles of males and females with relapsing MS and healthy controls. We will analyze microRNA (miRNA) profiles using NanoString and correlate them with mRNA levels to better understand the role of miRNAs in MS etiopathogenesis. Aim 2b: Explore associations between clinical features and RNA-seq and miRNA data. We will explore the relationship between significantly differentially expressed miRNA and mRNA profiles and clinical features (MRI activity, CSF biomarkers, and disability).This is the first study to narrow the phenotype of MS by using homogeneous human samples to measure and compare sex-based differences in MS. Results of this study are expected to shed light on MS phenotypes, and to inform future study design in larger cohorts with the potential for ultimately improving the quality of care in this population.