Functional role of ATF4 in physiological and inflammation induced oligodendroglial cellular senescence

• Applicant: Professorin Dr. Tanja Kuhlmann
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521608544

Multiple sclerosis is the most frequent demyelinating disease affecting the adult CNS and a leading cause for permanent disability in young adults. Relapsing remitting MS can successfully be treated by a range of immune-modulating drugs primarily interfering with lymphocyte activation and proliferation as well as immune cell transmigration across the BBB, thereby indirectly targeting the inflammatory processes within the CNS. However, treatment of the progressive disease phase is still an unmet need. One reason for the so far unsuccessful attempts to target disease progression, is our limited understanding of the the exact pathomechanisms underlying disease progression. Emerging concepts suggest that a combination of persisting focal and diffuse inflammation within the CNS and a gradual failure of compensatory mechanisms including remyelination together results in MS disease progression. The disease course can be further modified by patient intrinsic factors, such as age. Based on preliminary results, we want to address here the hypotheses that 1. chronic inflammation present in the brains of MS patients results in accelerated cellular senescence, impaired functions and increased cell death susceptibility of oligodendrocytes and 2. that ATF4 is an important driver of physiological and immune mediated oligodendroglial senescence. To address these objectives, we will use directly converted human oligodendrocytes, primary mouse cultures, an demyelinating animal model as well spatial transcriptomics analyses of human tissue sections.

• DFG Programme: Research Grants