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（由申请人提供）：在过去的40年中，哮喘和过敏性疾病的患病率急剧增加。因此，确定调节过敏/哮喘的机制至关重要，以确定干预的新目标。我们最近证明，补充5-羟化性物种（5HTP）会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5-羟色胺，但许多报道表明5HTP和5-羟色胺的给药在生理反应上的结果相反。 5HTP的合成减少与焦虑/抑郁有关。有趣的是，有许多临床报告表明焦虑/抑郁症与过敏/哮喘有关联，但这种关联的机制尚不清楚。 还据报道，在过敏原挑战的啮齿动物中，焦虑症增加，表明潜在的协调调节。我们提出了一个新的概念，即在过敏/哮喘期间的白细胞募集和焦虑/抑郁症可以通过补充5HTP协调降低。 将5HTP代谢为5-羟色胺，然后血清素结合抑制性或刺激性5-羟色胺受体（HTRS）或5-羟色胺与蛋白质共价链接（血清素化）。 与我们的新概念一致，我们报告说5HTP减少过敏性炎症，降低过敏原诱导的内皮细胞中的血清素化，并降低过敏原诱导的AHR。在体外，内皮细胞的5HTP预测阻止了白细胞跨内皮迁移，并阻止了细胞因子刺激的内皮细胞血清素化，表明5HTP的反馈调节负反馈。 我们的长期目标是确定过敏/哮喘中白细胞募集5HTP调节的机制，从而确定潜在的过敏性炎症和相关焦虑/抑郁症状的潜在靶标。为了朝着我们的长期目标迈出的一步，我们的中心假设是，易于使用的氨基酸补充剂5HTP（来自植物性的植物谷原简化）通过5HTP抑制内皮细胞信号限制了白细胞募集，因此依赖嗜酸性AHR和过敏蛋白诱发的焦虑症。我们将以以下特定目的测试中心假设：目标1。测试了内皮细胞和/或白细胞上HTR的假设介导5HTP的5HTP抑制白细胞跨内皮迁移的体外迁移。 AIM 2。检验以下假设：5HTP在VCAM-1依赖性白细胞跨内皮迁移的体外抑制内皮细胞中VCAM-1细胞内信号。 目标3。检验5HTP抑制白细胞募集，AHR和相关抗原引起的焦虑升高的假设，通过5HTP的HTRS或血清素化调节。预计目的将确定 5HTP抑制过敏性炎症，过敏原诱导的AHR和焦虑。 预计此类结果将产生重要的积极影响，因为除了促进对5HTP炎症调节的机械理解之外，还可能确定干预的新目标。