Grant: Project Grant

Multiple sclerosis (MS) is a disease in which the immune system mistakenly attacks the brain and spinal cord, confusing them with being a bacteria or virus. While current drugs can control MS in its early phases, the later, progressive form is very difficult to treat. There is no cure for MS, and thus studying the factors that control its incidence and severity is very important. To study these, we have developed a new model of MS in which mice show relapses as well as a chronically worsening progressive phase. Biological sex plays an important role in many diseases, and MS is no exception; however, its role in MS is perhaps paradoxical. Overall, women are more likely to develop MS; but men are more prone to transitioning to a progressive form, and to suffering worsened outcomes. Sex effects arise from the actions of sex hormones (e.g., estrogen vs. testosterone) or chromosomes (XX vs. XY). While the effects of sex hormones are perhaps better appreciated, we are beginning to understand that chromosomes also have important roles in biology. Using our mouse model, we have found that while male chromosomes (i.e., XY) worsen MS-like disease, male hormones make it better. Thus, our hypothesis is that a see-saw balance between the effects of hormones and chromosomes might explain the complex role of sex in MS. In this project, we will identify genes on the X and chromosomes that can worsen (or improve) disease in mice. We will also study how sex hormones can impact important cell signaling pathways in our mice. Importantly, we will study the identified genes in cells that are taken from people living with MS. Overall, we aim to better understand how sex can affect MS incidence and severity, with the goal of developing new drug targets and precision-medicine approaches.