Identifying changes to cellular physiology that drive multiple sclerosis risk

• Applicant: Dr. Christiane Gasperi
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: Funded in 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428832948

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). The pathophysiology of MS is multifactorial and most likely driven primarily by an inappropriate immune response mounted against components of myelin in the CNS leading to demyelination and at later stages to neurodegeneration. Over the last twenty years, research focused on T helper cells as driving MS pathology but more recently, both experimental and clinical evidence has implicated B cells as additional drivers of pathology. MS risk is heritable and over 200 of genetic factors across the entire human genome encoding this risk have been identified. The cellular mechanisms driving MS risk are yet to be understood and a central challenge now is to translate the genetic findings into an understanding of the pathophysiology of disease risk. It has previously been shown that most of disease-associated loci perturb gene regulation rather than gene structure and many of the loci encode components of a limited number of signaling cascades primarily associated with immune responses and cytokine signaling. The aim of this project is to link genetic factors for MS risk with alterations in the cellular physiology of different immune cell types including B cells and helper T cells. This will be investigated using Joint likelihood mapping (JLIM), a recently developed robust method to determine whether two different traits are driven by the the same underlying genetic effect. We will use JLIM and data of immune cell phenotypes that have already been shown to have a genetic basis, gene expression data from T cells, B cells and monocytes and MS risk data to uncover immune cell phenotypes relevant to MS pathophysiology. This could give us a better understanding of this complex disease and could potentially facilitate the development of new treatment strategies.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Chris Cotsapas, Ph.D.