5 -Hydroxytryptophan Regulation of Endothelial Cell Signals for Lung Inflammation

5-羟基色氨酸对肺部炎症内皮细胞信号的调节

• 批准号: 8577431
• 负责人: JOAN M COOK-MILLS
• 金额: $ 36.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577431
• 关键词: 5-Hydroxytryptophan; Actins; Address; Affinity; Allergens; Allergic; Allergic Disease; Allergic inflammation; Amino Acids; Antigens; Anxiety; Asthma; Basophils; Binding; Cell Adhesion Molecules; Cell Communication; Cells; Clinical; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Endothelial Cells; Enzymes; Equilibrium; Feedback; Genetic Polymorphism; Glutamine; Goals; Griffonia; Human; Hypersensitivity; In Vitro; Inflammation; Intervention; Leukocytes; Link; Lung; Lung Inflammation; Mediating; Mental Depression; Metabolism; Molecular; Mus; Outcome; Physiological; Plants; Prevalence; Proteins; Regulation; Reporting; Rodent; Serotonin; Severities; Signal Transduction; Structure of parenchyma of lung; Supplementation; Testing; Transglutaminases; Vascular Cell Adhesion Molecule-1; airway hyperresponsiveness; allergic response; cytokine; depressive symptoms; eosinophil; in vivo; innovation; mast cell; migration; novel; polymerization; public health relevance; response; serotonin receptor

DESCRIPTION (provided by applicant): The prevalence of asthma and allergic diseases has dramatically increased in the last 40 years. Therefore, it is critical to determine mechanisms for regulation of allergy/asthma in order to identify novel targets for intervention. We recently demonstrated that 5-hydroxytryptophan (5HTP) supplementation inhibits allergic lung inflammation and allergen-induced airway hyperresponsiveness (AHR). Cells metabolize 5HTP to serotonin but many reports indicate that 5HTP and serotonin administration have opposite outcomes on physiological responses. Reduced synthesis of 5HTP is associated with anxiety/depression. Interestingly, there are many clinical reports indicating an association of anxiety/depression with allergy/asthma, but the mechanism for this association is not known. It is also reported that anxiety is increased in rodents challenged with allergen, suggesting a potential coordinated regulation. We propose a novel concept that leukocyte recruitment and anxiety/depression during allergy/asthma are coordinately reduced by 5HTP supplementation. 5HTP is metabolized to serotonin and then serotonin binds inhibitory or stimulatory serotonin receptors (HTRs) or serotonin is covalently linked to proteins (serotonylation). Consistent with our novel concept, we reported that 5HTP reduced allergic inflammation, decreased allergen-induced serotonylation in endothelial cells and reduced allergen-induced AHR. In vitro, 5HTP-pretreatment of endothelial cells blocked leukocyte transendothelial migration and blocked cytokine-stimulated endothelial cell serotonylation, suggesting a negative feedback regulation by 5HTP. Our long-term goal is to identify mechanisms for 5HTP regulation of leukocyte recruitment in allergy/asthma and thus identify potential targets for intervention in allergic inflammation and the associated anxiety/depression symptoms. As a step towards our long-term goal, our central hypothesis is that the readily available amino acid supplement 5HTP (from the plant Griffonia Simplifolia) limits leukocyte recruitment through 5HTP inhibition of endothelial cell signals and consequently eosinophil-dependent AHR and allergen-induced anxiety. We will test our central hypothesis with the following specific aims: Aim 1. Test the hypothesis that HTRs on endothelial cells and/or leukocytes mediate 5HTP inhibition of leukocyte transendothelial migration in vitro. Aim 2. Test the hypothesis that 5HTP inhibits VCAM-1 intracellular signals in endothelial cells during VCAM-1-dependent leukocyte transendothelial migration in vitro. Aim 3. Test the hypothesis that 5HTP inhibits leukocyte recruitment, AHR and the associated antigen-induced elevation of anxiety through 5HTP regulation of HTRs or serotonylation. It is anticipated that the aims will identify mechanisms for 5HTP inhibition of allergic inflammation, allergen-induced AHR and anxiety. Such results are expected to have an important positive impact, because it is likely that new targets for intervention will be determined in addition to advancing the mechanistic understanding of 5HTP regulation of inflammation.

描述(申请人提供)：哮喘和过敏性疾病的流行在过去的40年里急剧增加。因此，为了确定新的干预靶点，确定过敏/哮喘的调节机制是至关重要的。我们最近证实，补充5-羟色氨酸(5HTP)可抑制过敏性肺部炎症和过敏原诱导的气道高反应性(AHR)。细胞将5-HTP代谢为5-羟色胺，但许多报道表明，5-HTP和5-羟色胺对生理反应的影响是相反的。5HTP合成减少与焦虑/抑郁有关。有趣的是，有许多临床报告表明焦虑/抑郁与过敏/哮喘有关，但这种联系的机制尚不清楚。另有报道称，用变应原挑战的啮齿动物焦虑增加，这表明可能存在协调调节。我们提出了一个新的概念，即补充5htp可以协同减少过敏/哮喘期间的白细胞募集和焦虑/抑郁。5HTP被代谢成5-羟色胺，然后5-羟色胺与抑制性或刺激性5-羟色胺受体(HTR)或5-羟色胺与蛋白质共价连接(5-羟色胺)。与我们的新概念一致，我们报告了5HTP减少过敏性炎症，减少过敏原诱导的内皮细胞5-羟色胺基化，并减少过敏原诱导的AHR。在体外，5HTP可阻断白细胞经内皮细胞的迁移，并阻断细胞因子刺激的内皮细胞5-羟色胺基化，提示5HTP具有负反馈调节作用。我们的长期目标是确定5HTP在过敏/哮喘中调节白细胞募集的机制，从而确定干预过敏性炎症和相关焦虑/抑郁症状的潜在靶点。作为我们迈向长期目标的一步，我们的中心假设是，现成的氨基酸补充剂5htp(来自植物Griffia Simplifolia)通过抑制内皮细胞信号，从而抑制嗜酸性粒细胞依赖的AHR和过敏原诱导的焦虑来限制白细胞的募集。我们将通过以下具体目标来检验我们的中心假说：目的1.检验内皮细胞和/或白细胞上的HTRs在体外介导5HTP抑制白细胞跨内皮细胞迁移的假说。目的2.验证5HTP在依赖VCAM-1的白细胞经内皮细胞迁移过程中抑制内皮细胞内VCAM-1信号的假说。目的3.验证5HTP通过调节hTRs或5-羟色胺来抑制白细胞募集、AHR及相关抗原引起的焦虑升高的假说。预计目标将确定以下机制： 5HTP可抑制过敏性炎症、过敏原诱导的AHR和焦虑。这些结果有望产生重要的积极影响，因为除了推进5HTP对炎症调控的机制理解外，很可能还将确定新的干预靶点。