Subproject Investigator: Celine A. Beamer

子项目研究员：Celine A. Beamer

• 批准号: 9322425
• 负责人: CELINE A BEAMER
• 金额: $ 21.75万
• 依托单位: UNIVERSITY OF MONTANA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9322425
• 关键词: ARNT gene; Activities of Daily Living; Adrenal Cortex Hormones; Adverse effects; Affect; Affinity; Agonist; Alpha Cell; Amino Acids; Apoptosis; Aryl Hydrocarbon Receptor; Asthma; Attention; Autoimmune Diseases; Autoimmunity; BHLH Protein; Behavior; Bilirubin; Binding; Binding Sites; Biological Assay; Biological Process; Biological Response Modifiers; Cell Cycle Progression; Cell Differentiation process; Cell physiology; Cells; Chronic; Custom; Development; Disease; Equilibrium; Etiology; Foundations; Gene Expression Profiling; Genetic Transcription; Health; Healthcare; Homology Modeling; Human; Immune; Immunobiology; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Interleukin-17; Knowledge; Ligand Binding; Ligand Binding Domain; Ligands; Link; Lung; Lymphoid Cell; Modeling; Molecular; Molecular Conformation; Mucous Membrane; Mus; Pathway interactions; Photoaffinity Labels; Play; Population; Population Heterogeneity; Prevention; Production; Protein Family; Proteins; Pulmonary Inflammation; Receptor Activation; Receptor Signaling; Research Personnel; Role; Route; Signal Pathway; Specificity; Structure; System; Testing; Therapeutic; Tissues; Toxic effect; airway hyperresponsiveness; airway inflammation; analog; aryl hydrocarbon receptor ligand; base; cytokine; design; immune function; immunoregulation; in vivo; inflammatory lung disease; insight; interleukin-22; novel; novel therapeutics; pathogen; receptor structure function; response; small molecule; transcription factor

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.

哮喘等炎症性肺部疾病影响着全球近 3 亿人，包括 约占美国人口的 11%。目前，慢性炎症性肺部疾病可以得到控制，但 未治愈；因此，它们成为长期医疗保健最昂贵的疾病之一。一个标志 慢性气道炎症是细胞因子的增加，引起肺部和气道炎症 过度反应。目前的治疗方法主要是使用皮质类固醇来抑制 炎症虽然有效，但具有显着的副作用。一个潜在的强大方法是 细胞因子反应的小分子操纵。 芳烃受体 (AhR) 是属于 Per-ARNT-SIM 的配体激活转录因子 (PAS)-碱性螺旋-环-螺旋 (bHLH) 蛋白家族，调节免疫细胞分化和功能 对天然和合成配体的反应。 AhR 与结构多样的配体相互作用，导致 对先天淋巴细胞（ILC）分泌细胞因子的不同影响。我们的初步结果支持 前提是 AhR 配体的功能差异可用于操纵调节因子的表达 （例如 IL-22）与气道炎症中炎症细胞因子（例如 IL-17）的比较，从而减少炎症。如果我们可以设计 选择性诱导第 3 组 ILC 产生 IL-22 的小分子，应该有可能促进这种作用 效应，并利用这些知识开发治疗炎症性肺部疾病的新疗法。 因此，该项目将重点了解 YH439 和定制设计的机制 类似物激活 AhR 并诱导 ILC 中 IL-22 的表达，从而产生无毒的免疫反应 调节作用。然后，我们将创建一种新颖的光亲和探针，其目的是：1）询问 AhR- 配体相互作用，2) 阐明 AhR 结构、功能和构象变化，以及 3) 识别新的 或蛋白质中的替代结合位点。该项目的成功完成所产生的成果是 预计支持这样的概念：肺部 AhR 信号通路的调节会影响 通过改变 ILC 的功能来控制炎症性疾病的进展。