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.

项目概要 传染性和非传染性疾病期间炎症的严格调节对于限制组织至关重要 死盒解旋酶家族成员被称为视黄酸- 诱导型基因 I 样受体（RIG-I 样受体，RLR）在识别自我和非自我方面发挥着关键作用 宿主细胞胞浆中的核酸及其下游干扰素 (IFN) 的失调。 尽管炎症信号级联反应可以表现为自身免疫或抗菌反应缺陷。 RLR、这些受体的功能及其相关的分子途径在 不同的细胞类型，在我们对组织稳态与疾病状态的理解中仍然存在重要差距。 作为一名独立研究者，我现在的研究重点是 RLR 的新兴非规范功能和 干扰素在肺部发病机制和免疫细胞编程这两个关键的背景下调节炎症 更好地了解 RLR 相关信号传导可能会导致新的治疗策略 我们的初步研究发现，感染性和非感染性炎症性疾病。 使用合成激动剂的 RLR RIG-I 的 RLR RIG-I 会导致免疫细胞编程基因的激活，而不是 此外，我们还发现了 III 型干扰素 (IFN●) 在肺组织修复中的新作用。 我的研究计划可以通过三个主题目标来定义：1）阐明如何进行。 RLR 和 IFN 通路有助于组织稳态，2) 确定 RLR 和 IFN 通路是否 在受损组织和邻近组织中精心选择的一组细胞类型中被差异激活，以及 3) 确定 RLR 和 IFN 在控制非感染性或感染介导性方面的独特贡献 我们开发了首个小鼠模型来消除炎症的表达。 RLR RIG-I、MDA5 及其下游信号转导接头 MAVS，以及 I 型和 III 型 IFN 信号转导 这些工具将使我们能够使用尖端的高参数。 光谱细胞术以及空间转录组学，以确定最相关的炎症途径 最终，我们的研究是由单个细胞类型在其自然组织微环境中部署的。 将增进对核酸传感途径的细胞内在调控的理解，并提供策略 针对每个途径进行差异化治疗，以最大限度地提高治疗效果，同时最大限度地减少不良副作用。