Subproject Investigator: Celine A. Beamer

哮喘等炎症性肺部疾病影响全球近3亿人，包括 约占美国人口的11%。目前，慢性炎症性肺部疾病是可以控制的，但 没有治愈；因此将它们置于长期医疗保健最昂贵的疾病之列。的一个标志 慢性气道炎是引起肺部和呼吸道炎症的细胞因子的增加。 反应过度。目前的治疗方法围绕着使用皮质类固醇来抑制 炎症，虽然有效，但有显著的副作用。一种潜在的有效方法是 细胞因子反应的小分子操纵。 芳香烃受体(AhR)是一种配体激活的转录因子，属于Per-Arnt-SIM (PAS)-碱性-螺旋-环-螺旋(BHLH)蛋白家族，调节免疫细胞的分化和功能 对天然和合成配体的反应。AhR与结构不同的配体相互作用，导致 天然淋巴样细胞(ILCs)对细胞因子分泌的不同影响。我们的初步结果支持 假设AhR配体的功能差异可能被利用来操纵调节性基因的表达 (例如，IL-22)与炎症(例如，IL-17)细胞因子在呼吸道炎症中的作用，从而减少炎症。如果我们能设计出 由第3组ILC选择性诱导IL-22产生的小分子，应该可以促进这一点 效果，并利用这一知识开发治疗炎症性肺部疾病的新疗法。 因此，本项目将重点了解YH439和定制设计的 类似物激活AhR并诱导ILCs表达IL-22，导致无毒免疫- 调节作用。然后，我们将创建一种新型的光亲和探针，用于：1)询问AhR- 配体相互作用，2)阐明AhR的结构、功能和构象变化，3)鉴定新的 或蛋白质中的替代结合部位。本项目圆满完成后产生的成果如下 预期支持肺中AhR信号通路的调制影响 炎症性疾病的进展通过改变ILC的功能能力。

Inflammatory lung diseases such as asthma affect nearly 300 million people worldwide, including approximately 11% of the U.S. population. Currently, chronic inflammatory lung diseases can be controlled, but not cured; thus placing them among the most expensive diseases for long-term healthcare. A hallmark of chronic airway inflammation is the increase in cytokines that provoke inflammation in the lung and airway hyper-responsiveness. Current therapies revolve around the use of corticosteroids for suppression of inflammation, which while effective, have significant side effects. A potentially powerful approach would be small molecule manipulation of the cytokine response. The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor belonging to the Per-ARNT-SIM (PAS)-basic-helix-loop-helix (bHLH) protein family that modulates immune cell differentiation and function in response to natural and synthetic ligands. The AhR interacts with structurally diverse ligands resulting in differential effects on cytokine secretion by innate lymphoid cells (ILCs). Our preliminary results support the premise that functional differences in AhR ligands may be exploited to manipulate the expression of regulatory (e.g. IL-22) vs. inflammatory (e.g. IL-17) cytokines in airway inflammation, thus reducing it. If we can design small molecules that selectively induce IL-22 production by group 3 ILCs, it should be possible to promote this effect, and use this knowledge to develop novel therapies for inflammatory lung diseases. Therefore, this project will focus on understanding the mechanisms by which YH439 and custom-designed analogs activate the AhR and induce the expression of IL-22 in ILCs, leading to a non-toxic immune- modulatory action. We will then create a novel photoaffinity probe for the purposes of: 1) interrogating AhR- ligand interactions, 2) elucidating AhR structure, function, and conformation changes, and 3) identifying novel or alternative binding sites in proteins. The results generated from the successful completion of this project are expected to support the concept that modulation of AhR signaling pathways in the lungs impacts the progression of inflammatory diseases by altering the functional capacity of ILCs.