Mechanisms of pathologically enforced CBM signaling in inflammatory skin disease

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The main objective of this project is to elucidate the pathophysiological mechanisms of aberrant CARD14 function and enforced BCL10 / MALT1 signaling in inflammatory skin disease. To this end, we generated a series of novel mouse lines that allow for controlled activation and inactivation of CBM signaling components in keratinocytes in vivo and in vitro. We will use these tools to address the following specific aims.Specific aim (1): We want to determine if the constitutively active CBM signaling triggered by CARD14 mutants is sufficient to drive inflammatory skin disease. In parallel, we will utilize CARD11 variants as genetic tools for controlled CBM activation. We will characterize the respective disease phenotypes and determine whether CARD14 variants signal exclusively through BCL10 and MALT1 or if they also engage CBM-independent pathways in keratinocytes.Specific aim (2): We want to investigate the molecular and cellular consequences of constitutive CBM signaling in keratinocytes in vivo and in vitro to elucidate the mechanisms by which this pathway drives keratinocyte activation and skin inflammation. In particular, we want to characterize the precise downstream signaling pathways activated by mutated CARD14 and the factors that are secreted by mutated keratinocytes in vivo.Specific aim (3): We plan to study the keratinocyte-specific functions of CBM signaling in a chemically (imiquimod-) induced psoriasis-like disease model to define general roles of this pathway in skin inflammation beyond genetically triggered CARD14 signaling.Specific aim (4): We plan to validate our results in psoriasis patient-derived tissue samples. In particular, we will test if related pathways or specific targets of the enhanced CBM signaling are differentially regulated in human psoriasis.