Mechanisms of pathologically enforced CBM signaling in inflammatory skin disease

本项目的主要目的是阐明CARD 14功能异常和BCL 10/MALT 1信号转导在炎症性皮肤病中的病理生理机制。为此，我们产生了一系列新的小鼠品系，其允许在体内和体外角质形成细胞中CBM信号传导组分的受控激活和失活。具体目标（1）：我们想确定由CARD 14突变体触发的组成型活性CBM信号传导是否足以驱动炎症性皮肤病。同时，我们将利用CARD 11变体作为受控CBM激活的遗传工具。我们将描述各自的疾病表型，并确定CARD 14变体是否仅通过BCL 10和MALT 1信号传导，或者它们是否也参与角质形成细胞中的CBM非依赖性途径。具体目标（2）：我们希望研究角质形成细胞中组成性CBM信号传导的分子和细胞后果，以阐明该途径驱动角质形成细胞活化和皮肤炎症的机制。特别是，我们希望表征由突变的CARD 14激活的精确下游信号通路和由突变的角质形成细胞在体内分泌的因子。我们计划用化学方法研究角质形成细胞特有的CBM信号功能，（咪喹莫特-）诱导的银屑病-类似的疾病模型，以定义该途径在皮肤炎症中的一般作用，而不是遗传触发的CARD 14信号传导。我们计划在银屑病患者来源的组织样本中验证我们的结果。特别是，我们将测试相关的途径或特定的目标，增强CBM信号在人类银屑病的差异调节。

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.