Background: Phagocytes play a dual role in inflammation and recovery of the CNS.
Hypothesis: Paracrine phagocyte derived signals are critical checkpoints for neuronal recovery in models of toxic and inflammatory injury.
Strategy: Develop and apply mass spectrometry-based proteomics tools to dissect the communication between phagocytes and CNS derived cells.
Communication between immune cells, glia and neurons regulate homeostatic and disease states in the central nervous system (CNS). One major challenge in this context is to decipher how immune cell derived signals can induce the formation and perpetuation of destructive tissue inflammation, while signals from the same cells are also essential in promoting the resolution of inflammation and subsequent tissue repair. Due to technical limitations in studying intercellular communication comprehensively, it is however still unclear, how paracrine signalling is altered during the induction and resolution of CNS disease states. Our research project aims at developing advanced mass spectrometry-based proteomics tools to dissect signals exchanged between phagocytes and CNS resident cells in order to identify molecular checkpoints of neuro-recovery in mouse models of toxic and inflammatory injury. In particular, we plan to pursue the following specific aims:
Aim ❶ Development of proteomics tools to study intercellular communication in the CNS
We will establish novel proteomics technologies for the comprehensive analysis of phagocyte-CNS communication based on secreted proteins, truncated proteins variants, and total cellular proteomes ex vivo as well as in vivo.
Aim ❷/❸ Dissecting phagocyte-CNS communication during recovery from CNS injury
We will apply our proteomics discovery tools to identify paracrine signals exchanged between resident as well as infiltrating phagocytes and major CNS tissue resident cells. We will compare two distinct mouse models of CNS inflammation, which differ in their immunological response pattern as well as in the outcome of the recovery process to identify shared and distinct checkpoints of CNS recovery: We will dissect phagocyte-CNS communication during lesion formation and resolution in a model of autoimmunity and during successful versus failed lesion resolution in a model of toxic demyelination.
Aim ❹ Functional phagocyte-CNS signalling networks during CNS recovery
We will further explore options to target identified proteomic alterations and disease-associated communication structures in vitro, in collaboration with CRC investigators, who provide access to and expertise in analyzing these models of CNS disease. Altogether, this project will establish a system-level view of intercellular signalling in the CNS and will generate new hypotheses about how phagocyte-CNS signals regulate tissue inflammation and recovery.