Regulation of host cell inflammatory and maturation response through AdV DNAdete

描述（由申请人提供）：在当前的提案中，我们正在表征细胞溶质DNA传感器的DNA识别如何协调炎性小体和I型干扰素（IRF 3）激活的抗病毒级联的激活。我们提出细胞溶质DNA传感器蛋白AIM 2是激活这两个级联的关键。使用重组腺病毒载体感染巨噬细胞系或原代细胞，我们正在确定如何触发DNA传感机制信号激活IRF 3 I型干扰素应答，并影响这些抗原呈递细胞的成熟。基于初步的数据，我们表明，DNA传感器响应的重要下游目标之一是衔接蛋白STING。将检查支持炎性小体/STING靶标的DNA传感器共激活的支架。目前的提议提出了这样的假设，即AIM 2的功能是平衡抗原呈递细胞的抗病毒反应。我们已经发现，干扰素诱导基因AIM 2也通过STAT 1参与调节I型干扰素敏感性。我们提出了一个AIM 2/STAT 1调节环功能，以控制目标免疫哨兵细胞的炎症/IFN敏感性。本提案中提出的研究针对的是重组腺病毒载体的先天性和适应性免疫应答的核心免疫识别应答途径。我们提出这些途径在免疫细胞中以特定的方式运作。从这些研究中获得的知识将有助于增强疫苗，基因治疗和抗癌治疗应用，并有助于我们开发病毒感染和宿主DNA依赖性自身免疫性疾病的新治疗方法。

DESCRIPTION (provided by applicant): In the current proposal we are characterizing how DNA recognition by cytosolic DNA sensors coordinates activation of both the inflammasome and type I Interferon (IRF3) activated antiviral cascades. We are proposing the cytosolic DNA sensor protein AIM2 is pivotal to activation of both cascades. Using recombinant adenovirus vector infection of macrophage cell lines or primary cells, we are determining how triggering the DNA sensing machinery signals activation of the IRF3 type I interferon response and influences maturation of these antigen presenting cells. Based on preliminary data, we show that one of the essential downstream targets of the DNA sensor response is the adaptor protein STING. The scaffolds that support DNA sensor co-activation of inflammasome/STING targets will be examined. The current proposal presents the hypothesis that AIM2 is functioning to balance the antigen-presenting cell antiviral response. We have found that AIM2 which is an interferon inducible gene is also involved in regulating type I interferon sensitivity through STAT1. We are proposing an AIM2/STAT1 regulatory loop functions to control the inflammatory/IFN sensitivity of target immune sentinel cells. The studies presented in this proposal are targeting the immune recognition response pathways that are at the heart of the innate and adaptive immune response to recombinant adenovirus vectors. We are proposing these pathways are operating in a specific manner in immune cells. The knowledge gained from these studies will contribute to enhancing vaccine, gene therapy, and anticancer therapeutic applications and they will contribute to our ability to develop new treatments for viral infections and host DNA dependent autoimmune diseases.