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

项目总结 在感染性和非感染性疾病中严格控制炎症对于限制组织是至关重要的。 在促进疾病解决的同时，促进疾病的发展。被称为维甲酸的死盒解旋酶家族成员- 可诱导的基因I样受体(RIG-I样受体，RLRs)在识别自我和非我中起着关键作用 宿主细胞胞浆中的核酸。RLR及其下游干扰素(干扰素)和 炎症信号级联反应可表现为自身免疫或抗菌反应的缺陷。尽管 RLRs的重要作用，这些受体的功能及其相关的分子通路在 不同的细胞类型，仍然是我们理解组织动态平衡与疾病状态的一个重要差距。 作为一名独立研究员，我现在的研究重点是RLRs和RLRs的新出现的非规范功能 干扰素调节炎症在肺部发病机制和免疫细胞编程方面的两个关键 更好地理解RLR相关信号可能导致新的治疗策略的领域 传染性和非传染性炎症性疾病。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 干扰素诱导。此外，我们还确定了III型干扰素(干扰素)在下列肺组织修复中的新作用 病原体诱导的损伤。我的研究计划可以用三个主题目标来定义：1)阐明如何 RLR和干扰素途径有助于组织动态平衡，2)决定RLR和干扰素途径是否 在受损组织和邻近组织中，在战略上选择的一组细胞类型中差异激活，以及3) 确定RLR和干扰素在控制非感染性或感染介导性方面的不同作用 炎症和消退。我们已经开发了第一个小鼠模型来消除表达 RLRs RIG-I、MDA5及其下游信令适配器MAV，以及I型和III型干扰素信令 以时间和细胞特有的方式进行的通路。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，以确定最相关的炎症途径 由单个细胞类型在其自然组织微环境的背景下部署。最终，我们的研究 将提高对核酸传感通路的细胞内在调控的理解，并将提供策略 用于针对不同的途径，以最大限度地提高治疗效益，同时将不良副作用降至最低。

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.