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

基本信息

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
项目类别：
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

项目摘要

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）：在当前的建议中，我们表征了胞质DNA传感器识别DNA识别如何协调炎症体和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对于两个级联反应的激活都是关键的。使用巨噬细胞系或原代细胞的重组腺病毒载体感染，我们确定如何触发IRF3 I型干扰素反应的DNA传感机械信号激活并影响这些抗原呈现细胞的成熟。基于初步数据，我们表明DNA传感器响应的基本下游靶标之一是衔接蛋白刺激。将检查支持支持DNA传感器共同激活炎症/刺激目标的脚手架。当前的提案提出了以下假设：AIM2在抗原抗原细胞抗病毒反应之间起作用。我们发现，AIM2是干扰素诱导基因的AIM2，还参与了通过STAT1调节I型干扰素敏感性。我们提出了AIM2/STAT1调节环函数，以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是针对先天性和适应性免疫反应对重组腺病毒载体的核心的免疫识别反应途径。我们提出这些途径在免疫细胞中以特定方式运行。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，它们将有助于我们开发针对病毒感染和宿主DNA依赖DNA的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，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）免疫反应的一个新的且知之甚少的区域。在当前的提案中，我们正在研究由鼠巨噬细胞的RADV感染触发的DNA感应网络。我们在这个令人兴奋而重要领域的研究将有助于免疫修饰策略，能够增强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。