Regulation of TLR Signaling and Innate Immunity by RP105

RP105 对 TLR 信号传导和先天免疫的调节

• 批准号: 7650111
• 负责人: Christopher L Karp
• 金额: $ 36.79万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650111
• 关键词: Antibodies; Antigen-Presenting Cells; B Cell Proliferation; B-Lymphocytes; Bacillus anthracis; Binding; Biological; Biological Assay; Biology; Bleomycin; Categories; Cell physiology; Cells; Complex; Data; Dendritic Cells; Dependence; Disease; Failure; Filoviridae; Generations; Goals; Hand; Homologous Gene; Immune; Immune response; In Vitro; Infection; Infection Control; Infectious Agent; Inflammation; Inflammatory Response; Lead; Leishmania; Ligands; Lipopolysaccharides; Literature; Lymphocyte Antigen 96; Mediating; Modeling; Molecular; Molecular Structure; Mus; Myeloid Cells; Natural Immunity; Pathogenesis; Pathology; Pattern; Physiological; Process; Production; Publishing; Reagent; Receptor Signaling; Regulation; Renaissance; Research Personnel; Role; Sepsis; Sepsis Syndrome; Signal Pathway; Signal Transduction; Structure; Surface; TLR4 gene; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Vaccination; Work; Yersinia pestis; crosslink; cytokine; in vivo; in vivo Model; inhibitor/antagonist; injured airway; macrophage; microbial; novel; pathogen; programs; receptor; response

DESCRIPTION (provided by applicant): Toll-like receptors (TLRs) are signaling receptors that are central to innate immune recognition of a variety of pathogens. Activation of TLR signaling by conserved microbial structures promotes the induction of innate immune responses. Such responses must be kept under tight control. Responses that are disrupted, delayed, or of insufficient vigor can lead to a failure to control infection. On the other hand, excessive or inappropriate inflammation can be harmful or even fatal- something seen in the hyper-activation of innate immune responses that marks microbial sepsis. Innate immune dysregulation is thought to be central to the pathogenesis of the diseases caused by diverse Category A and B biological threat agents. Conversely, well-regulated innate immune responses are thought to be key to successful host responses to these pathogens, as well as to successful vaccination against these and other infectious agents. Signaling through TLRs is tightly regulated. We recently discovered a novel mechanism of TLR counter- regulation- the TLR4 homolog, RP105. We have found that: (a) RP105 expression mirrors that of TLR4 on antigen presenting cells; (b) RP105 is a specific inhibitor of TLR4 signaling in HEK293 cells; (2) RP105 interacts directly with TLR4, inhibiting the ability of the TLR4 signaling complex to bind lipopolysaccharide (LPS); (3) RP105 regulates TLR4 signaling in dendritic cells and macrophages; (4) RP105 regulates in vivo responses to LPS; and (5) RP105 acts as a biologically important inhibitor of TLR4 signaling in both microbial and non-microbial models of inflammation. The central hypothesis underlying these studies is that RP105 is a physiological regulator of TLR4 signaling and TLR4-driven immune responses. The long-term goal of this work is to define the molecular mechanisms that underlie the generation and regulation of successful immune responses to biological threat agents and other pathogens. The studies in this proposal will characterize, both in vitro and in vivo, the capacity of RP105 to modulate TLR signaling and TLR-driven immune responses. We will: (1) Define the molecular mechanisms and biological consequences of RP105- mediated modulation of TLR signaling in myeloid cells; (2) Determine the mechanisms responsible for modulation of B cell function by RP105; and (3) Define the role of RP105 in regulating TLR4 signaling in response to endogenous ligands.

描述(申请人提供)：Toll样受体(TLRs)是信号受体，对各种病原体的天然免疫识别至关重要。TLR信号被保守的微生物结构激活，促进了先天免疫反应的诱导。这样的反应必须受到严格控制。反应中断、延迟或活力不足可能导致无法控制感染。另一方面，过度或不适当的炎症可能是有害的，甚至是致命的--这体现在先天性免疫反应的过度激活，这是微生物败血症的标志。先天免疫失调被认为是由不同的A类和B类生物威胁因子引起的疾病的发病机制的核心。相反，调节良好的先天免疫反应被认为是宿主对这些病原体成功反应的关键，也是成功接种这些和其他感染性病原体疫苗的关键。通过TLR发送的信号受到严格监管。我们最近发现了一种新的TLR反调节机制-TLR4同源物，RP105。我们发现：(A)RP105在抗原提呈细胞上的表达反映了TLR4在抗原提呈细胞上的表达；(B)RP105是HEK293细胞中TLR4信号的特异性抑制物；(2)RP105直接与TLR4相互作用，抑制TLR4信号复合体结合脂多糖(LPS)的能力；(3)RP105调节树突状细胞和巨噬细胞中的TLR4信号；(4)RP105调节体内对LPS的反应；以及(5)RP105在微生物和非微生物炎症模型中都是TLR4信号的重要抑制因子。支持这些研究的中心假设是RP105是TLR4信号和TLR4驱动的免疫反应的生理调节因子。这项工作的长期目标是确定成功地产生和调节对生物威胁因子和其他病原体的免疫反应的分子机制。该方案中的研究将在体外和体内表征RP105调节TLR信号和TLR驱动的免疫反应的能力。我们将：(1)确定RP105介导的髓系细胞TLR信号调节的分子机制和生物学意义；(2)确定RP105调节B细胞功能的机制；(3)确定RP105在内源性配体调节TLR4信号中的作用。