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: 8711545
• 负责人: JOAN M COOK-MILLS
• 金额: $ 37.85万
• 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/8711545
• 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（由申请人提供）：过去 40 年来，哮喘和过敏性疾病的患病率急剧增加。因此，确定过敏/哮喘的调节机制以确定新的干预目标至关重要。我们最近证明，补充 5-羟色氨酸 (5HTP) 可以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 5HTP 代谢为血清素，但许多报告表明 5HTP 和血清素给药对生理反应有相反的结果。 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/哮喘存在关联，但这种关联的机制尚不清楚。 另据报道，受到过敏原挑战的啮齿动物的焦虑感增加，这表明潜在的协调调节。我们提出了一个新概念，即通过补充 5HTP 来协调减少过敏/哮喘期间的白细胞募集和焦虑/抑郁。 5HTP 代谢为血清素，然后血清素与抑制性或刺激性血清素受体 (HTR) 结合，或者血清素与蛋白质共价连接（血清素化）。 与我们的新概念一致，我们报道 5HTP 减少过敏性炎症，减少过敏原诱导的内皮细胞血清素化，并减少过敏原诱导的 AHR。在体外，内皮细胞的5HTP预处理阻断了白细胞跨内皮迁移并阻断了细胞因子刺激的内皮细胞血清素化，表明5HTP的负反馈调节。 我们的长期目标是确定过敏/哮喘中 5HTP 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/抑郁症状的潜在目标。作为实现我们长期目标的一步，我们的中心假设是，现成的氨基酸补充剂 5HTP（来自 Griffonia Simplifolia 植物）通过 5HTP 抑制内皮细胞信号来限制白细胞的募集，从而限制嗜酸性粒细胞依赖性 AHR 和过敏原诱导的焦虑。我们将测试我们的中心假设，具体目标如下： 目标 1. 测试内皮细胞和/或白细胞上的 HTR 在体外介导白细胞跨内皮迁移的 5HTP 抑制的假设。目标 2. 检验以下假设：在体外 VCAM-1 依赖性白细胞跨内皮迁移过程中，5HTP 抑制内皮细胞中的 VCAM-1 细胞内信号。 目标 3. 检验以下假设：5HTP 通过 5HTP 调节 HTR 或血清素化来抑制白细胞募集、AHR 以及相关抗原诱导的焦虑升高。预计目标将确定机制 5HTP 抑制过敏性炎症、过敏原引起的 AHR 和焦虑。 这样的结果预计将产生重要的积极影响，因为除了推进对 5HTP 炎症调节机制的理解之外，很可能还会确定新的干预目标。