RIG-I-like receptor regulation of pulmonary inflammation and homeostasis

RIG-I 样受体对肺部炎症和稳态的调节

• 批准号: 10711053
• 负责人: Emily Ann Hemann
• 金额: $ 39.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711053
• 关键词: Agonist; Area; Autoimmunity; Cells; Cytometry; Cytosol; Defect; Discrimination; Disease; Family member; Genes; Genetic; Goals; Homeostasis; Immune; Individual; Infection; Inflammation; Inflammatory; Interferons; Knock-out; Lung; Mediating; Molecular; Mus; Nucleic Acids; Pathogenesis; Pathology; Pathway interactions; Play; Pulmonary Inflammation; Regulation; Research; Research Personnel; Resolution; Retinoic Acid Receptor; Role; Signal Pathway; Signal Transduction; Therapeutic; Tissues; Tretinoin; antimicrobial; cell type; helicase; immune activation; improved; mouse model; novel; pathogen; prevent; programs; receptor; receptor function; repaired; response; sensor; side effect; tissue repair; tool; transcriptomics

PROJECT SUMMARY Stringent regulation of inflammation during infectious and non-infectious diseases is critical for limiting tissue pathology while promoting disease resolution. The dead-box helicase family members known as retinoic acid- inducible gene I-like receptors (RIG-I-like receptors, RLRs) play a critical role in recognizing self and non-self nucleic acids in the cytosol of host cells. Dysregulation of RLRs and their downstream interferon (IFN) and inflammatory signaling cascade can manifest as autoimmunity or as defects in antimicrobial responses. Despite the critical importance of RLRs, the function of these receptors and their associated molecular pathways in different cell types, remains an important gap in our understanding of tissue homeostasis versus diseased states. As an independent investigator, my studies now focus on how emerging non-canonical functions of RLRs and IFN regulate inflammation in the context of pulmonary pathogenesis and immune cell programming, two critical areas in which better understanding of RLR-associated signaling could lead to new strategies for treating infectious and non-infectious inflammatory diseases. Our preliminary studies have found that atypical induction of the RLR RIG-I using a synthetic agonist leads to activation of immune cell programming genes rather than IFN induction. Moreover, we have identified new roles for type III IFN (IFN) in pulmonary tissue repair following pathogen-induced damage. My research program can be defined with three thematic goals: 1) elucidate how RLRs and IFN pathways contribute to tissue homeostasis, 2) determine whether RLR and IFN pathways are differentially activated in a strategically-selected set of cell types in damaged vs adjacent tissues, and 3) determine the distinct contributions of RLR and IFN in controlling non-infectious or infection-mediated inflammation and resolution. We have developed first-of-their-kind mouse models to eliminate expression of the RLRs RIG-I, MDA5, and their downstream signaling adapter MAVS, as well as type I and type III IFN signaling pathways in temporal and cell-specific fashions. These tools will allow us to use cutting edge high-parameter spectral cytometry, along with spatial transcriptomics, to define the most relevant inflammatory pathways deployed by individual cell types in the context of their natural tissue microenvironment. Ultimately, our studies will improve understanding of cell-intrinsic regulation of nucleic acid sensing pathways, and will provide strategies for differentially targeting each pathway to maximize therapeutic benefit while minimizing adverse side effects.

项目摘要 严格调节传染病和非感染性疾病期间的炎症对于限制组织至关重要 病理学同时促进疾病解决。死盒解旋酶家族成员称为视黄酸 - 诱导基因i样受体（RIG-I样受体，RLR）在识别自我和非自我方面起着关键作用 宿主细胞的胞质醇中的核酸。 RLR及其下游干扰素的失调（IFN）和 炎症信号传导级联反应可能表现为自身免疫性或抗菌反应中的缺陷。尽管 RLR的关键重要性，这些接收器的功能及其相关的分子途径 不同的细胞类型仍然是我们对组织体内稳态与患病状态的理解的重要差距。 作为一名独立研究者，我的研究现在集中于RLR和 IFN在肺部发病机理和免疫核管编程的背景下调节炎症，两个关键 更好地了解与RLR相关信号的领域可能会导致治疗的新策略 传染性和非感染性炎症性疾病。我们的初步研究发现非典型诱导 使用合成激动剂的RLR RIG-1的rig-i导致免疫细胞编程基因的激活而不是激活 IFN诱导。此外，我们已经确定了III型IFN（IFN的新作用（IFN）在肺组织修复中 病原体引起的损害。我的研究计划可以通过三个主题目标来定义：1）阐明如何 RLR和IFN途径有助于组织稳态，2）确定RLR和IFN途径是否为 差异激活在策略性选择的损伤中与相邻组织中的细胞类型，3） 确定RLR和IFN在控制非感染或感染介导的不同的贡献 炎症和分辨率。我们已经开发了首先的鼠标模型，以消除 RLRS RIG-I，MDA5及其下游信号适配器MAV以及I型和III型IFN信号传导 临时和细胞特异性时尚中的途径。这些工具将使我们能够使用最前沿的高参数 光谱细胞仪以及空间转录组学，以定义最相关的炎症途径 由单个细胞类型在其天然组织微环境的背景下部署。最终，我们的研究 将改善对核酸传感途径的细胞中性调节的理解，并将提供策略 针对每种途径的不同，以最大程度地提高热益处，同时最大程度地减少不良副作用。