Regulation of host cell inflammatory and maturation response through AdV DNAdete

通过 AdV DNAdete 调节宿主细胞炎症和成熟反应

• 批准号: 8084949
• 负责人: ERIK S FALCK-PEDERSEN
• 金额: $ 42.25万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8084949
• 关键词: Adaptor Signaling Protein; Adenovirus Vector; Adenoviruses; Affect; Antigen-Presenting Cells; Antiviral Agents; Antiviral Response; Area; Autoimmune Diseases; Biological Assay; Biological Models; Biology; Capsid; Cell Line; Cell membrane; Cells; Complement; DNA; DNA Vaccines; Data; Disease; Equilibrium; Event; Experimental Models; Exposure to; Gene Transfer; Genes; Heart; Hepatocyte; IRF3 gene; Immune; Immune System Diseases; Immune Targeting; Immune response; In Vitro; Infection; Inflammatory; Integrins; Interferon Type I; Interferons; Knock-out; Knowledge; Laboratories; Ligation; Link; Modeling; Modification; Mus; Participant; Pathway interactions; Proteins; Protocols documentation; Recombinants; Regulation; Research; Role; STAT1 gene; Sentinel; Signal Transduction; TBK1 gene; TNF gene; Testing; Therapeutic; Translating; Vaccines; Viral; Virus Diseases; adenovirus penton protein; anti-cancer therapeutic; arm; autocrine; base; biological adaptation to stress; defective adenoviral vector; design; gene therapy; gene transfer vector; high throughput screening; immune activation; immune function; in vitro Model; in vivo; macrophage; novel; paracrine; programs; research study; response; scaffold; sensor; small hairpin RNA; vector; virus host interaction

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. PUBLIC HEALTH RELEVANCE: Immune stimulating (is) DNA directly impacts immune function in DNA vaccines, DNA dependent autoimmune diseases and antiviral Immune responses. isDNA is a new and poorly understood area of the host (antiviral) immune response. In the current proposal we are investigating the DNA sensing networks triggered by rAdV infection of murine macrophages. Our research in this exciting and important area will contribute to immune modification strategies able to enhance the potency of DNA vaccines, enhance DNA vector gene transfer, or suppress DNA induced inflammatory diseases.

描述(由申请人提供)：在当前的提案中，我们正在描述胞液DNA传感器识别DNA如何协调炎症小体和I型干扰素(IRF3)激活的抗病毒级联反应的激活。我们提出胞质DNA传感器蛋白AIM2是激活这两个级联的关键。利用重组腺病毒载体感染巨噬细胞系或原代细胞，我们正在确定触发DNA传感机制如何信号激活I型干扰素反应，并影响这些抗原提呈细胞的成熟。基于初步数据，我们表明DNA传感器响应的一个重要下游靶标是接头蛋白刺突。将检查支持DNA传感器共同激活炎症小体/刺靶的支架。目前的建议提出了一种假设，即AIM2发挥着平衡抗原提呈细胞抗病毒反应的功能。我们发现，作为干扰素诱导基因的AIM2也通过STAT1参与了I型干扰素敏感性的调节。我们提出了一个AIM2/STAT1调控环功能，以控制靶免疫哨兵细胞的炎症/干扰素敏感性。这项建议中提出的研究针对的是免疫识别反应途径，这些途径是对重组腺病毒载体的先天和获得性免疫反应的核心。我们提出，这些途径在免疫细胞中以特定的方式运行。从这些研究中获得的知识将有助于加强疫苗、基因治疗和抗癌治疗应用，它们将有助于我们开发针对病毒感染和宿主DNA依赖型自身免疫性疾病的新疗法。 公共卫生相关性：免疫刺激(IS)DNA直接影响DNA疫苗、依赖DNA的自身免疫性疾病和抗病毒免疫反应中的免疫功能。IsDNA是宿主(抗病毒)免疫反应中一个新的、知之甚少的区域。在目前的提案中，我们正在研究由rAdV感染小鼠巨噬细胞而触发的DNA传感网络。我们在这个令人兴奋和重要的领域的研究将有助于制定免疫修饰策略，从而提高DNA疫苗的效力，增强DNA载体的基因转移，或抑制DNA诱导的炎症性疾病。