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.

诸如哮喘等炎症性肺部疾病影响了全世界近3亿人，包括 约有11％的美国人口。目前，可以控制慢性炎症性肺部疾病，但 没有治愈；从而将它们置于长期医疗保健最昂贵的疾病中。一个标志 慢性气道炎症是激发肺和气道炎症的细胞因子的增加 高反应性。当前的疗法围绕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。潜在强大的方法将是 细胞因子反应的小分子操纵。 芳基烃受体（AHR）是属于Per-arnt-SIM的配体激活转录因子 （PAS） - 基本螺旋 - 环螺旋（BHLH）蛋白质家族，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 先天淋巴样细胞（ILC）对细胞因子分泌的差异作用。我们的初步结果支持 可以利用AHR配体的功能差异来操纵调节表达的前提。 （例如IL-22）与气道炎症中的炎症（例如IL-17）细胞因子，从而减少了炎症。如果我们可以设计 小分子选择性地诱导第3组ILC产生IL-22的小分子，应该有可能促进这一点 影响，并利用这些知识开发新的炎性肺部疾病疗法。 因此，该项目将集中于理解YH439和定制设计的机制 类似物激活AHR并诱导IL-22在ILC中的表达，导致无毒免疫 调节作用。然后，我们将为以下目的创建一个新颖的光性探针：1）询问AHR- 配体相互作用，2）阐明AHR结构，功能和构象变化，3）识别新型 或蛋白质中的替代结合位点。该项目成功完成产生的结果是 预计将支持肺中AHR信号通路的调节影响这样的概念 通过改变ILC的功能能力来进展。