Project Details
Projekt
Neuronal intracellular Ca2+ stores in inflammatory neurodegeneration.
Subject Area
Molecular and Cellular Neurology and Neuropathology
Term
from 2015 to 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262890264
Multiple sclerosis (MS) is the most frequent inflammatory disease of the CNS. Inflammatory insults lead to progressive degeneration of axons and neurons that is key for the development of permanent neurological disability. We recently discovered that the neuronal calcium-activated ion channel transient receptor potential melastatin 4 (TRPM4) crucially contributes to neurodegeneration by being activated under inflammatory conditions. However, the roles of other transient receptor potential (TRP) channels in guiding neurons toward survival or death during CNS inflammation are entirely unexplored. As TRP channels have a prominent role as environmental sensor proteins, we propose here to identify TRP channels that contribute directly or indirectly by altering immune responses or endothelial function to neuronal injury or protection. We have generated preliminary data showing that TRPV4 is strongly upregulated in inflamed CNS tissue and that Trpv4-deficient mice show an ameliorated disease course in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). In work package 1, we will concentrate on deciphering the mechanism how TRPV4 is contributing to the disease process. This is designed to provide insight into new general mechanisms and operation modes of TRPV4 channels for the pathogenesis of MS. Moreover, by pursuing our analysis of differentially expressed cation channels and regulators thereof in cells and tissues affected in the EAE model and by setting up the novel technique of genome editing using clustered regularly interspaced short palindromic repeats (CRISPR) in neuronal cells this will allow us in work package 2 to use an unbiased approach to identify novel regulators of calcium homeostasis and to directly functionally test their involvement in neurodegeneration or -protection. Together, our proposal will deliver a novel understanding of how neurodegeneration is regulated by TRP channels in CNS inflammation providing a basis for novel neuroprotective treatment strategies in MS.
DFG Programme
Research Units
