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，我们正在描述胞质 DNA 传感器的 DNA 识别如何协调炎症小体和 I 型干扰素 (IRF3) 激活的抗病毒级联的激活。我们提出胞质 DNA 传感器蛋白 AIM2 对于激活这两个级联至关重要。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 传感机制发出 IRF3 I 型干扰素反应激活信号并影响这些抗原呈递细胞的成熟。根据初步数据，我们表明 DNA 传感器响应的重要下游靶标之一是接头蛋白 STING。将检查支持 DNA 传感器共激活炎症小体/STING 靶标的支架。目前的提议提出了这样的假设：AIM2 的作用是平衡抗原呈递细胞的抗病毒反应。我们发现干扰素诱导基因AIM2也通过STAT1参与调节I型干扰素敏感性。我们提出 AIM2/STAT1 调节环路功能来控制目标免疫前哨细胞的炎症/IFN 敏感性。该提案中提出的研究针对的是免疫识别反应途径，该途径是对重组腺病毒载体的先天性和适应性免疫反应的核心。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，并将有助于我们开发针对病毒感染和宿主 DNA 依赖性自身免疫性疾病的新疗法的能力。 公共卫生相关性：免疫刺激 (is) DNA 直接影响 DNA 疫苗、DNA 依赖性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）免疫反应的一个新的、人们知之甚少的领域。在当前的提案中，我们正在研究由小鼠巨噬细胞的 rAdV 感染触发的 DNA 传感网络。我们在这一令人兴奋且重要的领域的研究将有助于制定免疫修饰策略，从而增强 DNA 疫苗的效力、增强 DNA 载体基因转移或抑制 DNA 诱导的炎症性疾病。