Influence of environmental factors on the interplay of transcriptome and proteome in newly diagnosed Multiple Sclerosis patients

• Applicants: Professor Dr. Nicholas Schwab, Ph.D.; Professor Dr. Heinz Wiendl
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445569437

Multiple sclerosis is an inflammatory disease of the central nervous system and the most common cause for disability in young adults with a prevalence of more than 2.5 million cases. Environmental factors have been shown to play a role for disease susceptibility and –severity. These factors include, but are not limited to smoking, diet, alcohol consumption and sun exposure. Several pathways have been suggested to mediate the effects of singular stimuli. However, it has long been assumed that specific nodal checkpoints act as mediators between the environment and the immune system, and it is possible that such nodes are triggered by different stimuli. As environmental factors are believed to be at least as important for multiple sclerosis susceptibility and -severity as genetics, it is of high (clinical) interest to unveil the regulatory network responsive to environmental cues. In the last decade, novel high-throughput methods have been developed that make it possible to screen an organisms’ transcriptome and proteome with high resolution in an unbiased manner. We here propose to use such methods including next-generation RNA sequencing and high-throughput mass spectrometry to unravel specific and superordinate networks/-regulators that mediate the effects of environmental factors and to search for correlations with markers of disease severity. For this, we will use biomaterial and clinical data from an existing, well-defined and homogenous cohort of n=120 MS patients in a large-scale systems biology approach that will be complemented with data from questionnaires on exposure to environmental stimuli. Factors of interested will include smoking, diet (in conjunction with body mass index), vitamin D levels (as a surrogate for sun-exposure), alcohol consumption, non-MS medication and the presence infectious diseases. In addition, we will acquire data from high-dimensional flow cytometry (20×10 marker matrix) from another project that will give insight into cellular immune architecture and how it is regulated by environmental factors. Once markers have been established, these will be correlated with clinical measures of disease severity (physical/-cognitive disability, fatigue, lesions and relapse rate) in cross-sectional and longitudinal analyses revealing markers of active disease and disease prognosis. We have prepared a systematic and exhaustive bioinformatical/statistical plan to answer these specific questions. In summary, we aim to use data generated from multiple high-throughput methods to unravel the factor-specific and superordinate patterns evoked by environmental factors on the MS peripheral blood immunome (transcriptome, proteome and leukocyte composition) and find correlates with disease activity and -progression. This might have implications for the development of biomarkers, but also for the discovery of novel therapeutic target molecules.

• DFG Programme: Research Grants