Project Details
Projekt
Genetic determinants of neurodegeneration during CNS inflammation
Applicants
Professorin Dr. Maja Jagodic; Pernilla Stridh, Ph.D.
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 523862973
Multiple sclerosis (MS) is a leading cause of progressive disability among young adults. The disease pathology is characterized by an infiltration of immune cells into the central nervous system (CNS), resulting in the destruction of myelin sheets and concomitant neurodegeneration. Despite recent advances in controlling early inflammatory stages of MS, the inevitable disease progression poses the greatest unmet clinical need. The underlying mechanisms remain largely unknown, underscoring the need to better understand the CNS-intrinsic mechanisms that sustain disease progression. We recently demonstrated that genetic variants affect disease trajectories in affected individuals. Thus, we hypothesise that the ability of neurons to survive and function under the inflammatory conditions is, to a considerable degree, under genetic control. Specifically, we aim to (A) identify candidate genes for MS severity for mechanistic studies, (B) establish the role of the hallmark genes of inflamed neurons in MS development, and (C) evaluate the relative contribution of immune vs. CNS reactions to MS progression. To that end, we have built the most powerful cohorts and datasets for genetic and mediation analysis. Genome-wide genotyping has already been completed in 14,500 MS cases from the Swedish cohort and 3,500 of them have also been whole genome sequenced, enabling imputation of > 40 million high quality genetic variants that will improve the precision of identified associations. Moreover, each individual has been linked with variables from nationwide registries, e.g., in- and outpatient visits, drug prescription codes, income, social benefits, educational attainment, that will be utilized to derive numerous measured and modelled disease outcome variables. These resources are further expanded or independently replicated through our active role in several international networks. Joining forces with NeuroFlame will provide highly relevant functional context for the mechanistic characterization of risk genes. The NeuroFlame expertise will facilitate the prioritization of candidate genes and conduct their functional characterization. In turn, we will investigate if the genes in hallmark pathways of inflamed neurons associate with MS outcomes, thus providing a strong link with their causal involvement in disease. Notably, identifying such genes will not only give insights into the molecular causes of neurodegeneration but also provide potential therapeutic targets to halt disease progression.
DFG Programme
Research Units
International Connection
Sweden
