Mechanisms of pathologically enforced CBM signaling in inflammatory skin disease

本项目的主要目的是阐明炎症性皮肤病中CARD14功能异常和Bcl10/MALT1信号增强的病理生理机制。为此，我们创造了一系列新的小鼠品系，允许在体内和体外控制角质形成细胞中CBM信号成分的激活和失活。我们将使用这些工具来解决以下特定目标。特定目标(1)：我们希望确定由CARD14突变体触发的结构性活跃的CBM信号是否足以驱动炎症性皮肤病。同时，我们将利用CARD11变种作为控制煤层气激活的遗传工具。我们将确定各自的疾病表型，并确定CARD14变异体是否仅通过Bcl10和MALT1发出信号，或者它们是否也参与角质形成细胞中的CBM非依赖性信号通路。具体目标(2)：我们想要研究体内和体外角质形成细胞中组成CBM信号的分子和细胞后果，以阐明该途径驱动角质形成细胞激活和皮肤炎症的机制。特别是，我们想要表征由突变的CARD14激活的准确的下游信号通路以及由突变的角质形成细胞在活体中分泌的因子。具体目标(3)：我们计划在化学(咪喹莫特)诱导的银屑病样疾病模型中研究CBM信号的角质形成细胞特异性功能，以确定除了遗传触发的CARD14信号之外，该通路在皮肤炎症中的一般作用。具体目标(4)：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增强的CBM信号的特定靶点在人类银屑病中是否存在差异调节。

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.