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 在感染性和非感染性疾病期间，炎症的严格调节对于限制组织 病理学，同时促进疾病的解决。死盒解旋酶家族成员视黄酸- 诱导型基因I样受体（RIG-I-like receptors，RLR）在识别自我和非自我中起着关键作用 宿主细胞胞质溶胶中的核酸。RLR及其下游干扰素（IFN）调节异常， 炎性信号级联可表现为自身免疫或抗微生物应答的缺陷。尽管 RLR的关键重要性，这些受体的功能及其相关的分子途径， 不同的细胞类型仍然是我们理解组织稳态与疾病状态的重要差距。 作为一个独立的研究者，我的研究现在集中在如何新兴的非典型功能的RLR和 IFN在肺部发病机制和免疫细胞编程的背景下调节炎症，这两个关键因素是 更好地理解与TLR相关的信号传导可能导致新的治疗策略的领域 感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-I导致免疫细胞编程基因的激活，而不是 IFN诱导。此外，我们已经确定了III型IFN（IFN γ）在肺组织修复中的新作用， 病原体引起的损伤我的研究计划可以定义为三个主题目标：1）阐明如何 RLR和IFN途径有助于组织内稳态，2）确定RLR和IFN途径是否是 在受损组织与邻近组织中的一组策略性选择的细胞类型中差异活化，以及3） 确定RLR和IFN在控制非感染性或感染介导的 炎症和消退。我们已经开发了第一种小鼠模型，以消除表达的 RLR RIG-I、MDA 5及其下游信号转导衔接子MAVS，以及I型和III型IFN信号转导 以时间和细胞特异性方式的途径。这些工具将使我们能够使用尖端的高参数 光谱细胞术，沿着空间转录组学，以确定最相关的炎症途径 由单个细胞类型在其天然组织微环境中部署。最终，我们的研究 将提高对核酸传感途径的细胞内在调节的理解，并将提供策略， 用于不同地靶向每种途径，以最大化治疗益处，同时最小化不良副作用。