The impact of Aryl hydrocarbon receptor signaling on Toll like receptor-mediated inflammation

芳基碳氢化合物受体信号传导对 Toll 样受体介导的炎症的影响

基本信息

批准号：
10569113
负责人：
CHRISTOPH F A VOGEL
金额：
$ 33.87万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-09 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569113
关键词：
Affect Antigen-Presenting Cells Aryl Hydrocarbon Receptor Asthma Autoimmune Diseases Autoimmunity B-Lymphocytes Binding Binding Sites Biological Bone Marrow Cell physiology Cells Chronic Disease Communicable Diseases Communication DNA Binding Data Dendritic Cells Development Dioxins Elements Environmental Pollutants Environmental Risk Factor Event Exposure to Future Gene Expression Gene Expression Profiling Genes Genetic Genome Goals Health Human Hypersensitivity IL12A gene Immune Immune System Diseases Immune response Immune system Immunity Immunoglobulin Fragments Immunologic Deficiency Syndromes Immunologic Monitoring Immunomodulators Immunosuppression Infection Inflammation Inflammatory Inflammatory Response Interleukin-1 beta Interleukin-6 Knockout Mice Lead Ligands Link Location Logic Lymphocyte Macrophage Maps Mediating Methods Modeling Molecular Monitor Mus NF-kappa B Outcome Pathologic Pathway interactions Physiological Play Positron-Emission Tomography Process Proteins REL Protein Radioimmunoconjugate Receptor Activation Receptor Signaling Regulation Regulatory T-Lymphocyte Reporting Repressor Proteins Role Scheme Shock Signal Pathway Signal Transduction Stimulus Surface Antigens T cell differentiation T-Cell Activation T-Lymphocyte Testing Time Tissues Toll-like receptors Toxic Environmental Substances Toxic effect Transcription Repressor Transgenic Mice Work aryl hydrocarbon receptor ligand cell type chromatin immunoprecipitation chronic inflammatory disease cytokine genome-wide analysis immune activation immune system function immunoreaction immunoregulation immunotoxicity in vivo innovation insight molecular targeted therapies monocyte mouse model mutant neutrophil novel overexpression pathogen protein protein interaction receptor recruit response sensor

项目摘要

Project Summary/Abstract The aryl hydrocarbon receptor (AhR) plays an important role in regulating immune responses and exposure to AhR-activating compounds, including environmental toxicants such as dioxins may contribute to the dysregulation of cytokines and the development of immune system disorders. The ligand-dependent activation of AhR can promote differentiation of inflammatory T helper Th17 cells or lead to profound immunosuppression and an increase of regulatory T cells. Significant gaps exist in our understanding of how the AhR regulates the inter- and intracellular communication processes between dendritic cells (DC) and other immune cells on the molecular level, which is of central importance to understanding both physiologic and pathophysiologic immune reactions mediated through AhR. The overall goal of this proposal is to identify the functional role of the AhR and its specific repressor (AhRR) interacting with Toll-like receptor (TLR) and NFkB signaling in controlling function and differentiation of DC and T-cell activation. The reported dysregulation of TLR and NFkB signaling by AhR ligands may be key steps in triggering immune system disorders. The transcriptional repressor of the AhR, the AhRR is implemented in the AhR pathway, although much remains to be elucidated at the level of TLR and NFkB signaling. In transgenic mice overexpressing AhRR we discovered that AhRR is critically involved in regulation of dioxin-induced inflammatory gene expression as well as LPS-mediated inflammatory responses and LPS shock. Thus, the AhRR Tg mice give us the opportunity to recognize how AhRR is involved in the regulation of TLR-mediated responses and other parts of the immune system. Bone-marrow derived DC from genetic mouse models as well as human DC, will be used to investigate how DC are regulated through ligand- induced activation of the AhR and inflammatory signals via TLR/NFkB. A genome-wide identification of AhR/Rel binding sites will be conducted and related to gene expression analysis. Mutants of binding sites will be generated to validate whether a particular binding event is actually required to regulate the expression of target genes. Protein-protein interaction studies will identify the specific interacting domains of AhR and Rel proteins and provide insight into how these interactions impact the functional activity of each protein and the outcome of AhR/NFkB crosstalk. A novel in vivo method to monitor immune responses noninvasively via Positron Emission Tomography (immuno-PET) imaging will be used to ultimately show how AhR ligands modify TLR-mediated recruitment and accumulation of DC, neutrophils, B cells, and T cells in vivo. This study can provide a definite link and mechanism between the exposure to AhR activating compounds and the development of inflammatory chronic diseases. Findings will allow for more clearly defined endpoints to assess the effects and toxicity of AhR activating ligands including environmental pollutants. This study will also provide new concepts for future innovative uses of AhR and AhRR as molecular targets for therapeutic applications in inflammation, infection, and chronic diseases.

项目摘要/摘要芳基烃受体（AHR）在调节免疫反应和暴露中起着重要作用 AHR激活化合物，包括环境有毒物质，例如二恶英可能有助于细胞因子的失调和免疫系统疾病的发展。配体依赖性激活 AHR可以促进炎症T助手Th17细胞的分化或导致深刻的免疫抑制并增加调节T细胞。我们对AHR如何调节的理解存在很大的差距树突状细胞（DC）和其他免疫细胞之间的细胞间和细胞内通信过程分子水平，这对于理解生理和病理生理免疫至关重要通过AHR介导的反应。该提案的总体目标是确定AHR的功能作用它在控制功能中与Toll样受体（TLR）和NFKB信号相互作用的特定阻遏物（AHRR） DC和T细胞激活的分化。据报道，AHR的TLR和NFKB信号失调配体可能是触发免疫系统疾病的关键步骤。 AHR的转录阻遏物， AHRR在AHR途径中实施，尽管在TLR的水平和 NFKB信号。在过表达AHRR的转基因小鼠中，我们发现AHRR与调节二恶英诱导的炎症基因表达以及LPS介导的炎症反应和LPS Shock。因此，AHRR TG小鼠使我们有机会认识AHRR如何参与 TLR介导的反应和免疫系统其他部分的调节。骨头arrow从遗传小鼠模型以及人类DC将用于研究如何通过配体调节DC 通过TLR/NFKB诱导AHR激活和炎症信号。全基因组识别AHR/REL的鉴定结合位点将进行并与基因表达分析有关。结合位点的突变体将是生成以验证是否实际需要特定的结合事件来调节目标的表达基因。蛋白质 - 蛋白质相互作用研究将确定AHR和REL蛋白的特定相互作用结构域并提供有关这些相互作用如何影响每种蛋白质的功能活性和结果的见解 AHR/NFKB串扰。一种新型的体内方法，可通过正电子发射来监测免疫反应层析成像（免疫-ET-PET）成像将最终显示AHR配体如何修改TLR介导 DC，中性粒细胞，B细胞和T细胞的募集和积累。这项研究可以提供明确的暴露于AHR激活化合物与炎症的发展之间的联系和机制慢性疾病。调查结果将允许更明确的终点来评估AHR的影响和毒性激活配体在内，包括环境污染物。这项研究还将为未来提供新的概念 AHR和AHRR作为炎症，感染，和慢性疾病。