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GABAA Receptor-Mediated Modulation of Lung Inflammation

GABAA 受体介导的肺部炎症调节

基本信息

批准号：
10320914
负责人：
Gene Thomas Yocum
金额：
$ 16.62万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-09 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320914
关键词：
Adoptive Cell Transfers Affect Agonist Airway Disease Airway Resistance Allergic Anesthetics Antiinflammatory Effect Asthma Biology Blood - brain barrier anatomy Bronchoalveolar Lavage Bronchoconstrictor Agents CD4 Positive T Lymphocytes Calcium Calcium Oscillations Calcium Signaling Cell Count Cell Proliferation Cell membrane Cell physiology Cells Chloride Channels Chlorides Chronic Complex Critical Illness Data Dendritic Cells Dermatophagoides Antigens Development Development Plans Disease Electrophysiology (science)Environment Epithelial Experimental Models Exposure to Extrinsic asthma Foundations Frequencies Gene Expression Histocytochemistry Human Image Imaging Techniques Immune Immune response Immunology Immunophenotyping In Situ In Vitro Inflammation Inflammatory Inhalation Intensive Care Units Ion Channel Knock-out Knockout Mice Ligands Link Lung Lung diseases Lymphocyte Lymphocyte Activation Lymphocyte Function Measures Mediating Membrane Membrane Potentials Mentors Monitor Mus Muscimol Nerve Nuclear Operating Rooms Pathway interactions Patients Pharmaceutical Preparations Phenotype Physicians Physiology Play Process Production Pulmonary Inflammation Pyroglyphidae Receptor Activation Receptor Signaling Research Science Scientist Signal Pathway Slice T cell therapy T-Cell Development T-Cell Receptor T-Lymphocyte Techniques Technology Therapeutic Training Universities Work airway hyperresponsiveness asthma model asthmatic career career development cell type chemokine clinically relevant clinically significant cytokine experimental study gamma-Aminobutyric Acid immune activation immune function immunoregulation in vivo mast cell migration mouse model new therapeutic target novel novel therapeutics positive allosteric modulator receptor respiratory smooth muscle sedative sensitizing antigen skills tool tumor

项目摘要

Project Summary/Abstract There is significant evidence that anesthetics which act at the GABAA receptor alter immune function and that multiple immune cell types express functional GABAA receptors. However, the mechanism of this immune modulation is unknown. In this proposal, we present exciting preliminary data demonstrating that mice lacking expression of the GABAA receptor α4 subunit (gabra4), a subunit expressed in immune cells including CD4+ lymphocytes, have significantly greater lung inflammation after sensitization with house dust mite antigen, a common allergic asthma model. This heightened inflammation results in greater in vivo airway reactivity. We also demonstrate that gabra4 knockout CD4+ cells express increased inflammatory cytokines compared to wild type CD4+ cells when stimulated via the T cell receptor in vitro, suggesting the hyper-inflammatory phenotype of the gabra4 knockout mouse may be CD4+ cell-mediated. We hypothesize that GABAA receptor currents, which are depolarizing in CD4+ cells, alter calcium signaling processes key in lymphocyte activation and function, specifically calcium oscillations and store-operated calcium entry. We propose to demonstrate that α4 subunit containing-GABAA receptors mediate currents in CD4+ cells which are augmented by GABAA receptor ligands, including XHE-III-74A, a novel α4 subunit selective positive allosteric modulator developed by a collaborator. We will also determine if the CD4+ cell is key in producing the gabra4 KO mouse’s hyper-inflammatory phenotype by performing adoptive T cell transfer experiments. Furthermore, we propose to determine if altered GABAAR signaling affects CD4+ cell calcium dynamics (oscillations and store operated calcium entry) using a novel in situ calcium imaging technique that utilizes precision-cut lung slice technology. This offers the key advantage of maintaining the native environment of the inflamed lung. Finally, we will determine if XHE-III-74A, an α4 subunit- selective GABAA receptor activator that does not cross the blood brain barrier, will limit house dust mite antigen induced lung inflammation and airway hyper-responsiveness when administered chronically during the sensitization process. Although the studies proposed here focus on lung inflammation, the implications of this work may be relevant to inflammatory processes of many types. Given the widespread use of GABAergic medications, this research promises to be of high clinical significance. My department and Columbia University provide an ideal environment to complete these studies, as all necessary support is already in place. In addition, my proven mentoring committee provides a perfect blend of skills to help guide the science, including expertise in ion channel physiology, lung biology, immunology, and calcium signaling. A comprehensive career development plan has been established, including coursework and additional training. Taken as a whole, this K08 proposal outlines a robust pathway to scientific independence and the foundation of a successful and sustained career as a physician-scientist.

项目总结/摘要有重要证据表明，作用于GABAA受体的麻醉剂改变免疫功能，多种免疫细胞类型表达功能性GABAA受体。然而，这种免疫的机制调制是未知的。在这项提案中，我们提出了令人兴奋的初步数据，表明缺乏 GABAA受体α4亚基（gabra 4）的表达，该亚基在包括CD 4 + T细胞在内的免疫细胞中表达，淋巴细胞在用屋尘螨抗原致敏后，肺部炎症显着增加，a 常见的过敏性哮喘模型。这种升高的炎症导致更大的体内气道反应性。我们还证明gabra 4敲除的CD 4+细胞表达的炎性细胞因子与野生型相比增加，在体外通过T细胞受体刺激时，CD 4 + T细胞的表达增加，表明 gabra 4敲除小鼠可以是CD 4+细胞介导的。我们假设GABAA受体电流，在CD 4+细胞中去极化，改变淋巴细胞活化和功能中关键的钙信号传导过程，特别是钙波动和钙库操作的钙进入。我们建议证明α4亚基含有GABAA受体的细胞介导CD 4+细胞中的电流，该电流被GABAA受体配体增强，包括XHE-III-74 A，一种由合作者开发的新型α4亚基选择性正变构调节剂。我们还将确定CD 4+细胞是否是产生gabra 4 KO小鼠的高度炎症表型的关键通过进行过继性T细胞转移实验。此外，我们建议确定是否改变GABAAR 信号传导影响CD 4+细胞钙动力学（振荡和钙池操作的钙进入），使用一种新的原位利用精确切割肺切片技术的钙成像技术。这提供了以下关键优势：维持发炎肺部的自然环境。最后，我们将确定XHE-III-74 A，一个α4亚基，选择性GABAA受体激活剂，不穿过血脑屏障，将限制屋尘螨抗原诱导的肺部炎症和气道高反应性，当长期给药期间，敏化过程。尽管这里提出的研究集中在肺部炎症，但这一研究的意义在于，工作可能与许多类型的炎症过程有关。鉴于GABA能的广泛使用因此，这项研究具有很高的临床意义。我的系和哥伦比亚大学提供一个理想的环境，以完成这些研究，因为所有必要的支持已经到位。此外，本发明还提供了一种方法，我的指导委员会提供了一个完美的技能组合，以帮助指导科学，包括专业知识，在离子通道生理学、肺生物学、免疫学和钙信号方面。一个全面的职业制定了发展计划，包括课程和额外培训。整体来看，这 K 08提案概述了实现科学独立的强大途径，以及成功和作为一名物理学家和科学家的职业生涯。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reduced allergic lung inflammation and airway responsiveness in mice lacking the cytoskeletal protein gelsolin.

减少缺乏细胞骨架蛋白凝溶胶蛋白的小鼠的过敏性肺部炎症和气道反应性。

DOI：
10.1152/ajplung.00065.2020
发表时间：
2020
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
0
作者：
Mikami,Maya;Yocum,GeneT;Heller,NicolaM;Emala,CharlesW
通讯作者：
Emala,CharlesW

Development of Inhaled GABAA Receptor Modulators to Improve Airway Function in Bronchoconstrictive Disorders.

开发吸入 GABAA 受体调节剂以改善支气管收缩性疾病的气道功能。

DOI：
10.1021/acsptsci.1c00238
发表时间：
2022
期刊：
ACS pharmacology & translational science
影响因子：
0
作者：
Zahn,NicolasM;Roni,MSRashid;Yocum,GeneT;Meyer,MichelleJ;Webb,DanielA;Mian,MdYeunus;Cook,JamesM;Stafford,DouglasC;Emala,CharlesW;Arnold,LeggyA
通讯作者：
Arnold,LeggyA

Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer.

DOI：
10.1002/ddr.21926
发表时间：
2022-06
期刊：
DRUG DEVELOPMENT RESEARCH
影响因子：
3.8
作者：
Roni, M. S. Rashid;Zahn, Nicolas M.;Yocum, Gene T.;Webb, Daniel A.;Mian, Md Yeunus;Meyer, Michelle J.;Tylek, Anika S.;Cook, James M.;Emala, Charles W.;Stafford, Douglas C.;Arnold, Leggy A.
通讯作者：
Arnold, Leggy A.