FOR 2289:  Calcium homeostasis in neuroinflammation and -degeneration: New targets for therapy of multiple sclerosis?

• Subject Area: Medicine ; Biology
• Term: from 2015 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 262890264

Recent paradigm shifts in our understanding of multiple sclerosis (MS) have led to opposing hypotheses about the sequence of pathophysiological events and the identity of cell types involved in disease initiation and propagation. Irrespective of whether MS is classified as being primarily either a neuroinflammatory, a neurodegenerative or a glial disorder, calcium signals are essential for the function of all cellular systems involved including the immune system, the neurovascular unit, glial cells and neurons/axons. Additionally, calcium is not only an important messenger within specific cells, but also serves as a crucial link between different ¿compartments¿ involved in MS pathophysiology. Due to its ubiquitous role throughout all tissues and its importance for intra- as well as intercellular and network functions, understanding disturbances in calcium homeostasis would allow both the simultaneous targeting of multiple pathophysiological mechanisms in addition to the development of cell type and context-specific therapies depending upon the pathways targeted.To this end, a team of researchers from diverse institutions and scientific fields has been assembled (comprising anatomy, biophysics, neurobiology, pharmacology, physiology as well as experimental and clinical neurology and neuroimmunology) to elucidate principle calcium-related disease mechanisms of MS, to develop cutting-edge methodologies including novel imaging techniques, and to identify new therapeutic targets. The anticipated synergistic outcome of the proposed Research Unit will have a profound impact on the understanding of acquired channelopathies, disturbances of calcium signaling and energy imbalance under neuroinflammatory and neurodegenerative conditions. Since this consortium is focused on as yet underestimated aspects of MS pathophysiology and applies a highly interdisciplinary approach, it is expected to break new ground in clinical neurology.

• DFG Programme: Research Units

Projects

• Ca2+-dependent synaptic signalling malfunctions in experimental optic neuritis. (Applicants Schmitz, Frank ;  Schwarz, Karin )
• Calcium and anatomical imaging of the live mouse retina during EAE: insights into the cascade of neurodegeneration (Applicants Fairless, Sarah ;  Winkler, Frank )
• Calcium-dependent T cell activation in multiple sclerosis (Applicants Alansary, Dalia ;  Niemeyer, Ph.D., Barbara Anne )
• Coordination Funds (Applicant Diem, Ricarda )
• Defective Ca2+ signalling between B cells and regulatory T cells: connecting the dots in the emergence of impaired peripheral B cell tolerance in multiple sclerosis? (Applicant Wildemann, Brigitte Theresia )
• Differential susceptibility of αRGCs to glutamate excitotoxicity in autoimmune optic neuritis (Applicants Draguhn, Andreas ;  Fairless, Richard )
• Does Cavβ3 subunit confer neuroprotection in chronic inflammatory CNS disease? (Applicants Diem, Ricarda ;  Flockerzi, Veit )
• Endothelial calcium signals in the control of neuroinflammation and neurodegeneration (Applicants Meuth, Sven G. ;  Platten, Michael )
• Histopathology Service (Applicant Fairless, Sarah )
• Neuronal intracellular Ca2+ stores in inflammatory neurodegeneration. (Applicants Freichel, Marc ;  Friese, Manuel A. )
• Role of Ca2+-dependent mitochondrial and endoplasmic reticulum dynamics for disease progression and neuroprotection in a model of multiple sclerosis. (Applicants Bading, Hilmar ;  Bas Orth, Carlos )
• Role of glial Ca2+ signals during neuroinflammation, axonal degeneration, and de- and remyelination in the mouse spinal cord – Part II (Applicants Kirchhoff, Frank ;  Scheller, Anja )
• Role of glutamate receptor-mediated Ca2+ signaling in regulating the fate of oligodendrocyte progenitors in multiple sclerosis (Applicant Agarwal, Ph.D., Amit )

• Spokesperson: Professorin Dr. Ricarda Diem