Host Defense and the Regulation of Interferon Production

宿主防御和干扰素产生的调节

• 批准号: 7891410
• 负责人: Glen N. Barber
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891410
• 关键词: Animals; Antibody Formation; Attention; Bacteria; Biological Response Modifiers; Boxing; Complex; Cytotoxic T-Lymphocytes; Data; Death Domain; Dendritic Cells; Differentiation Antigens; Disease; Double-Stranded RNA; Drosophila genus; Encephalomyocarditis virus; Exposure to; Family; Generations; Genes; Genetic Transcription; Grant; Host Defense; Host Defense Mechanism; IRF3 gene; Immune; Immune response; Immunotherapeutic agent; In Vitro; Infection; Interferon Type I; Interferons; Listeria monocytogenes; Mammalian Cell; Mediating; Microbe; Molecular; Natural Immunity; Pathway interactions; Pattern; Play; Process; Production; Protein Kinase; RNA Helicase; Regulation; Reporting; Research; Role; Screening procedure; Signal Pathway; Signal Transduction; Signaling Molecule; Therapeutic; Toll-like receptors; Transcription Factor 3; Transmembrane Domain; Tretinoin; Viral; Virus; Virus Diseases; Work; antimicrobial; cDNA Expression; computerized data processing; extracellular; fungus; gene function; helicase; human RIPK1 protein; human TLR3 protein; inhibitor/antagonist; insight; macrophage; melanoma; microbial; microorganism; novel; novel vaccines; pathogen; promoter; public health relevance; receptor; response; tumor

DESCRIPTION (provided by applicant): Host exposure to microbial pathogens such as viruses, bacteria and fungi trigger the activation of innate immune responses, including the production of type I interferon (IFN) that galvanize early host defense mechanisms as well as invigorate adaptive immune responses involving cytotoxic T cell activity and antibody production. The recognition of pathogenic microbes and the triggering of the innate immune cascade has become the subject of intense research over the past few years. Particular attention has recently focused on the role of the Toll-like receptors (TLRs), which have emerged as key molecules largely expressed by dendritic cells and macrophages, that are responsible for recognizing conserved components of pathogenic microorganisms (referred to as pathogen associated molecular patterns -PAMPs)- and which trigger the production of IFN. However, it has recently been discovered that critically important TLR-independent mechanisms also exist to thwart pathogen infection. Instrumental in these responses are a family of DExD/H helicases that appear critical for effective defense against virus infection. However, the mechanisms of TLR-independent signaling remain complex, with downstream molecular components responsible for facilitating the production of IFN remaining to be identified. Here, we have isolated a new molecule that appears to play a significant role in the regulation of innate immune signaling and which is critical for the production of IFN in response to pathogen infection. For this proposal we thus aim to study the importance of this molecule in innate immune helicase action. Essentially, we aim to: I: determine the importance of DExD/H helicases in innate immunity to pathogen infection, including mechanisms of action. II: To potentially determine the mechanisms of innate signaling mediated by the DExD/H helicases involved in pathogen recognition, we have effectively screened for novel molecules which activate the production of type I interferon (IFN), required for effective innate immunity. We aim to further characterize the importance of such molecules in innate signaling and aim to determine their mechanisms of action. These objectives will shed significant insight into the mechanisms of innate immune signaling and generate concepts useful for the generation of new vaccine and immunotherapeutic strategies. PUBLIC HEALTH RELEVANCE Our grant involves attempting to understand how the body recognizes diseases caused by viruses and bacteria. The proposal also aims to understand how the body induces an appropriate immune response following infection. By understanding these processes, we will gain insight into causes of disease and anticipate being able to develop new vaccine and therapeutic strategies. The study of LGP2 and STING and their interaction with other components in the pathway will provide significant insight about the molecular mechanism of RIG-I/MDA5-mediated IFN production and anti-viral innate immunity and thus is of high significance.

描述（由申请人提供）：宿主暴露于微生物病原体（例如病毒，细菌和真菌）触发先天免疫反应的激活，包括产生I型Interferon（IFN），从而激发了早期宿主防御机制以及涉及细胞毒性T细胞活性和抗体生产的适应性免疫反应。在过去的几年中，病原微生物的识别和先天免疫级联反应的触发已成为激烈研究的主题。最近，特别关注的是类似受体的受体（TLR）的作用，这些受体（TLR）已作为树突状细胞和巨噬细胞在很大程度上表达的关键分子出现，这些分子构成了识别病原性微生物的保守成分（称为病原体相关的分子模式 - 型 - pampamps-pampamps-pampamps），以及触发的生产。然而，最近已经发现，抑制病原体感染的至关重要的TLR独立机制也存在。在这些反应中的作用是DEXD/H解旋酶家族，对于有效防御病毒感染似乎至关重要。然而，独立于TLR的信号传导的机制仍然复杂，下游分子成分负责促进IFN的产生。在这里，我们分离了一个新的分子，该分子似乎在先天免疫信号传导的调节中起重要作用，这对于响应病原体感染的IFN产生至关重要。因此，对于这一提议，我们旨在研究该分子在先天免疫解旋酶作用中的重要性。从本质上讲，我们的目标是：I：确定DEXD/H解旋酶在先天免疫对病原体感染的重要性，包括作用机理。 II：潜在地确定由病原体识别的DEXD/H解旋酶介导的先天信号传导的机制，我们有效地筛选了激活I型干扰素（IFN）产生的新型分子，这是有效的先天性免疫所必需的。我们的目的是进一步表征这种分子在先天信号传导中的重要性，并旨在确定其作用机理。这些目标将对先天免疫信号传导的机制进行重大洞察力，并产生可用于生成新疫苗和免疫治疗策略的概念。 公共卫生相关性我们的赠款涉及试图了解身体如何识别病毒和细菌引起的疾病。该提案还旨在了解人体在感染后如何诱导适当的免疫反应。通过了解这些过程，我们将深入了解疾病的原因，并预计能够开发新的疫苗和治疗策略。 LGP2和Sting的研究及其与途径中其他成分的相互作用将为RIG-I/MDA5介导的IFN产生和抗病毒先天免疫的分子机制提供重大见解，因此具有很高的意义。