CARD-only protein regulation of cytosolic Pattern Recognition Receptor signaling

虽然急性炎症反应在先天免疫和宿主防御中具有保护作用， 失调和不能正确地解决这些反应会引起炎症和感染性疾病。 几种关键的胞质模式识别受体通过含有Caspase募集的蛋白质发出信号 结构域（CARD），其是蛋白质-蛋白质相互作用结构域，导致炎性小体和NF-κ B活化， 以及炎性细胞因子和I型干扰素（IFN）的产生。然而， 这些途径被控制以限制过度和有害的炎症反应， 未知 三种仅含一个CARD的小蛋白质，称为CARD纯蛋白（COP） 存在于人类中，但像相关的PYRIN结构域蛋白（POP）一样，缺乏小鼠， 支持了这些炎症反应需要严格控制的观点，特别是在人类中。警察 在十多年前就已经被发现，但是除了一些最初的过度表达研究， 这些蛋白质的确切作用。我们证明了这三种蛋白的关键炎性小体调节活性， 在人类和转基因小鼠中进行全面分析， 假设类似地，COPs将在调节炎症反应和我们的免疫应答中起重要作用。 初步数据表明，通过针对几种主要模式， 识别受体本提案中概述的研究旨在确定每届缔约方会议的确切作用 在巨噬细胞感染和炎症过程中，使用综合分析结合生化， 分子和遗传学方法。我们还将确定它们在炎症和传染病中的作用， 使用新产生的转基因小鼠进行所有三种COP。 我们希望我们的研究将揭示新的分子控制机制， 不适当的炎症，因此将是非常重要的和相关的更好地了解先天性 免疫和炎症性疾病，并为开发新的治疗方法提供基础， 患者，对人类健康产生积极影响。

Although, acute inflammatory responses have a protective role in innate immunity and host defense, dysregulation and failure to properly resolve these responses cause inflammatory and infectious disease. Several key cytosolic pattern recognition receptors signal through proteins containing the Caspase recruitment domain (CARD), which is a protein-protein interaction domain, leading to inflammasome and NF-kB activation, and inflammatory cytokine and type I interferon (IFN) production. However, the molecular mechanisms by which these pathways are controlled to limit excessive and detrimental inflammatory responses, are largely unknown. Three small proteins containing only a CARD, which are referred to as CARD-only proteins (COPs) exist in humans, but like the related PYRIN domain-only proteins (POPs), are lacking from mice, which supports the notion that these inflammatory responses require a tight control in particular in humans. COPs have been identified over a decade ago, but except of a few initial overexpression studies, nothing is known about the precise role of these proteins. We demonstrated key inflammasome regulatory activities of the three POPs encoded in humans using a comprehensive analysis in humans and transgenic mice, and we hypothesize that similarly, COPs will have an important role in regulating inflammatory responses and our preliminary data indicate that COPs have a broader role than POPs by targeting several key pattern recognition receptors. The research outlined in this proposal is geared to define the precise role of each COP in macrophages during infection and inflammation, using a comprehensive analysis combining biochemical, molecular and genetic approaches. We will also define their role during inflammatory and infectious disease, using novel generated transgenic mice for all three COPs. We expect that our research will uncover novel molecular control mechanisms that prevent inappropriate inflammation and will therefore be highly significant and relevant for better understanding innate immunity and inflammatory disease and for providing the basis for developing novel therapies to benefit patients and will therefore positively affect human health.