Abstract: MS is a complex disease involving both the immune system and the central nervous system (CNS). Females are more susceptible to MS than males, and immune responses are more robust in females. However, females do not demonstrate faster disability progression. Instead, being male is a risk factor for progression. Clearly immune responses and neurodegeneration must be studied independently with respect to sex differences in disease. This proposal will focus on the CNS. Irradiation bone marrow chimeras are a well established tool to manipulate the immune system independently from other tissues. We will use bone marrow chimeras to investigate sex differences in the CNS where there is no sex difference in the immune system. Sex differences will focus on a potential role for sex chromosomes, rather than sex hormones, by using mice that differ in sex chromosomes while having the same gonadal type. By varying sex chromosomes in chimeras reconstituted with a common immune system, one can ascertain the role of sex chromosomes on the CNS response to injury during experimental autoimmune encephalomyelitis (EAE), the most widely used model of MS. Four specific aims will address our overarching hypothesis that maternally inherited X chromosome gene(s) lead to more neurodegeneration in males compared to females, since these genes are expressed more in males who are XmY than females who are XmXp. In aim #1, we will determine how a difference in sex chromosomes affects gene expression in the CNS during EAE. In aim #2, we will determine how maternal versus paternal imprinting of the X chromosome affects DNA methylation and chromatin accessibility of genes in the CNS during EAE. In aim #3, we will use a CNS cell specific gene expression approach (RiboTag) to identify which sex chromosome genes differ in which cell in the CNS during EAE. In aim #4. We will determine the functional significance of sex chromosome genes that are differentially expressed in CNS cells during EAE. Together the above aims will identify sex chromosome gene(s) that lead to worse clinical and neuropathological disease. These findings will reveal new targets with the ultimate goal of finding a treatment to halt or slow neurodegeneration and disability progression in MS and potentially other neurological diseases.