Nicotinic Receptor Alpha 7 Regulation of Inflammation Induced by Cigarette Smoke

烟碱受体 Alpha 7 对香烟烟雾引起的炎症的调节

• 批准号: 9220696
• 负责人: LORISE C GAHRING
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9220696
• 关键词: Address; Alveolar; Alveolar Macrophages; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Brain; Calcium; Calcium Channel; Calcium Signaling; Calcium-Sensing Receptors; Caring; Cell Adhesion Molecules; Cells; Cigarette; Data; Electronic cigarette; Environmental Tobacco Smoke; Epithelial; Epithelial Cells; Exhibits; Fibrosis; Genetic Transcription; Goals; Hematopoietic; Immune; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Intervention; Lead; Lung; Lung diseases; Mediating; Medical Genetics; Mus; Nicotine; Nicotinic Receptors; Pathology; Patients; Peripheral; Permeability; Pharmacology; Predisposition; Process; Production; Proteomics; Pulmonary Pathology; Receptor Activation; Regulation; Reporting; Research; Risk; Signal Pathway; Signal Transduction; Smoking; System; Testing; Therapeutic Intervention; Time; Tissues; Veterans; Work; addiction; alpha-bungarotoxin receptor; chemokine; cigarette smoke-induced; cigarette smoking; cigarette smoking; clinically relevant; cytokine; environmental agent; environmental tobacco smoke exposure; granulocyte; inflammatory milieu; insight; interstitial; interstitial cell; macrophage; model design; mouse model; novel; patient population; public health relevance; receptor; response; transcription factor; transcriptome

DESCRIPTION (provided by applicant): The ultimate goal of this study is to define pharmacological interventions that impact the inflammatory state in the cigarette smoke exposed lung. The immune response in the lung is composed of tissue-specific responses often to environmental agents that require the coordinated response by multiple immune and non-immune cells. When this becomes dysregulated, then pathologies related to excessive pro-inflammatory responses or fibrosis can result. The VA patient population is particularly at risk because of the disproportionate number of individuals who use cigarettes. In the lung a major target of nicotine is the nicotinic acetylcholine receptor (nAChR) alpha7 (�. This receptor has an exceptionally high permeability to calcium that alone can modulate intracellular signaling pathways regulating of transcription factors, cytokines and chemokines. This project will use newly developed mouse models designed specifically to study the �inflammatory interaction with cigarette smoke (CS) in the mouse lung and will focus on identification of specific cellular signaling mechanisms controlling this response in alveolar and interstitial macrophages, as well as non-hematopoietic cells of the lung. The overall proposal hypothesis is: Modulation of the nicotinic �calcium current modifies tissue-specific intracellular signaling pathways in the lung in response to cigarette smoke. We will test this hypothesis in 3 Specific Aims: In Aim 1 the hypothesis is: Susceptibility to lung damage and compartmentalized inflammatory control is determined by cell-specific �expression. The preliminary data reveal that alveolar macrophages (AMs), granulocytes, and interstitial cells (hematopoietic and non-hematopoietic) express � and the expression level in individual animals corresponds to the magnitude of the inflammatory response. The results will for the first time allow us to define how CSand the nicotine in CS, acts through �to govern the inflammatory response by cells as they transition from a normal to a pro-inflammatory environment. In Aim 2 the hypothesis is: Calcium signaling through the �receptor activates cell signaling pathways that control the magnitude of the pro-inflammatory response. Newly developed mouse models that specifically restrict �calcium channel permeability will be used to define transcriptional and proteomic impacts of this restricted signaling on the nicotine:CS inflammatory response. Finally in Aim3 the hypothesis tested is: The �calcium mediated signaling pathway(s) contribute to expression of M-CSF and GM-CSF by both lung macrophages and alveolar epithelial cells. We have already found evidence of perturbation of the CSF-signaling system controlled by the �calcium signaling pathway. We will build upon this preliminary finding and apply our new findings to test the use of potential therapeutic interventions to manipulate the cellular responses dysregulated by CS and the nicotine: �nteraction to restore a more normal response. At the conclusion of this project we will offer novel insights into the mechanisms controlling the impact of CS on the lung and how the susceptibility to subsequent pathologies may be approached to impact upon this important VA patient issue.

描述(由申请人提供)： 这项研究的最终目标是确定影响香烟烟雾暴露肺炎症状态的药物干预措施。肺的免疫反应由组织特异性反应组成，通常是对环境因素的反应，这些反应需要多个免疫细胞和非免疫细胞的协调反应。当这种调节失调时，就会导致与过度的促炎反应或纤维化相关的病理。退伍军人症患者群体尤其危险，因为吸烟的个人数量不成比例。在肺部，尼古丁的一个主要靶点是烟碱型乙酰胆碱受体(NAChR)α7(�)。这种受体对钙具有极高的通透性，仅此一项就可以调节细胞内信号通路，调节转录因子、细胞因子和趋化因子。该项目将使用新开发的小鼠模型，专门研究�炎症与小鼠肺内香烟烟雾(CS)的相互作用，并将重点确定控制这种反应的特定细胞信号机制，包括肺泡和间质巨噬细胞以及肺的非造血细胞。总体建议假设是：尼古丁�钙电流的调节改变了肺组织特异性细胞内信号通路，以响应吸烟。我们将在3个具体目标中检验这一假设：在目标1中，假设是：对肺损伤和分区炎症控制的易感性由细胞特异性�的表达决定。初步数据显示，肺泡巨噬细胞(AM)、粒细胞和间质细胞(造血系和非造血系)表达�，并且在单个动物中的表达水平与炎症反应的大小相对应。结果将首次允许我们定义CS和CS中的尼古丁是如何起作用的 通过�来控制细胞从正常环境向促炎环境过渡时的炎症反应。在目标2中，假设是：通过�受体的钙信号激活细胞信号通路，控制促炎反应的大小。新开发的专门限制�钙通道通透性的小鼠模型将用于确定这种限制信号对尼古丁：CS炎症反应的转录和蛋白质组学影响。最后，在AIM3中验证的假设是：�钙介导的信号通路(S)有助于肺巨噬细胞和肺泡上皮细胞表达M-CSF和GM-CSF。我们已经发现了由�钙信号通路控制的脑脊液信号系统受到干扰的证据。我们将在这一初步发现的基础上，应用我们的新发现来测试潜在的治疗干预措施的使用，以操纵CS和尼古丁调节失调的细胞反应：�相互作用，以恢复更正常的反应。在本项目结束时，我们将提供控制CS对肺部影响的机制的新见解，以及如何处理对后续病理的易感性来影响这一重要的VA患者问题。