Resolution of Inflammation by the SIX-family Transcription Factors

项目摘要 本研究的重点是我们的发现，发育沉默的六家族转录 因子被TNF家族细胞因子重新激活，并有效抑制基因表达程序 由非典型NF-κ B诱导。首先描述人类细胞因子和病原体 相关分子模式（PAMPs）诱导Six 1和Six 2蛋白表达， 为了研究其重新激活所需的分子成分（目标1），这些研究将 揭示了哺乳动物免疫系统中非经典NF-kB调节的新途径。第二、 我们将确定Six蛋白如何通过启动子抑制炎症基因表达程序， 近端机制（目标2）。六种蛋白在炎症消退中的生理意义 虽然使用三种互补的小鼠模型在哺乳动物模型生物体中进行了研究， Six 1蛋白功能（目的3）。从这些研究中收集的见解将解释非经典NF-κ B如何在 kB在基因启动子处受到调节，并且还将揭示起重要作用的辅阻遏物复合物 在对微生物病原体的炎症反应中的作用。开发新的药物， 在微生物感染期间，SIX蛋白调节非典型NF-κ B的能力将是一种 对抗与NF-kB信号传导功能障碍相关人类疾病的创新方法， 慢性炎症因此，通过揭示SIX蛋白功能的分子细节， 哺乳动物的免疫系统，从生物化学到感染的小鼠模型，我们将揭示 可能被用于治疗干预的潜在弱点。重要的是，这些研究 还提供了新的见解的致病机制，一个重要的传染病引起的 代理人，也进入人体炎症反应的生物学。

Project Summary The present study focuses on our discovery that developmentally silenced SIX-family transcription factors are reactivated by TNF-family cytokines and potently suppress gene expression programs induced by non-canonical NF-kB. By first characterizing the human cytokines and pathogen associated molecular patterns (PAMPs) that induce Six1 and Six2 protein expression and by then investigating the molecular components required for their reactivation (Aim 1), these studies will reveal a new pathway for non-canonical NF-kB regulation in the mammalian immune system. Second, we will determine how Six-proteins inhibit inflammatory gene expression programs through promoter proximal mechanisms (Aim 2). Physiological significance of inflammatory resolution by Six-proteins while be investigated in mammalian model organisms using three complementary mouse models of Six1 protein function (Aim 3). Insights gleaned from these studies will explain how non-canonical NF- kB is regulated at gene promoters and will also reveal co-repressor complexes that play important roles in the inflammatory response to microbial pathogens. Developing new drugs that interfere with the ability of SIX proteins to regulate non-canonical NF-kB during microbial infection would be an innovative approach to combat human disease associated with NF-kB signaling dysfunction including chronic inflammation. Therefore, by revealing molecular details of SIX-protein function in the mammalian immune system, from biochemistry to mouse models of infection, we will uncover sites of potential weakness that may be exploited for therapeutic intervention. Importantly, these studies will also provide new insights into the pathogenic mechanisms of an important infectious disease-causing agent and also into the biology of the human inflammatory response.