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年里，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靶点至关重要。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5 -羟色胺，但许多报道表明5HTP和5 -羟色胺在生理反应上有相反的结果。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/哮喘有关，但这种联系的机制尚不清楚。也有报道称，啮齿动物受到过敏原的挑战时，焦虑会增加，这表明可能存在协调调节。我们提出了一个新的概念，即白细胞募集和过敏/哮喘期间的焦虑/抑郁通过补充5HTP而协调减少。5HTP被代谢为5 -羟色胺，然后5 -羟色胺结合抑制或刺激5 -羟色胺受体（HTRs），或者5 -羟色胺与蛋白质共价连接（5 -羟色胺化）。与我们的新概念一致，我们报道了5HTP减少过敏性炎症，减少内皮细胞中过敏原诱导的血清素化，减少过敏原诱导的AHR。体外5HTP预处理内皮细胞阻断白细胞跨内皮迁移，阻断细胞因子刺激的内皮细胞5 -羟色胺化，提示5HTP具有负反馈调节作用。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，从而确定过敏性炎症和相关焦虑/抑郁症状干预的潜在靶点。作为实现我们长期目标的一步，我们的中心假设是，易于获得的氨基酸补充剂5HTP（来自植物Griffonia Simplifolia）通过5HTP抑制内皮细胞信号，从而限制白细胞的募集，从而抑制嗜酸性粒细胞依赖性AHR和过敏原诱导的焦虑。我们将用以下具体目标来检验我们的中心假设：目标1。在体外验证内皮细胞和/或白细胞上的HTRs介导5HTP抑制白细胞跨内皮迁移的假设。目标2。验证5HTP在体外VCAM-1依赖性白细胞跨内皮迁移过程中抑制内皮细胞内VCAM-1信号的假设。目标3。通过5HTP调节HTRs或血清素化，验证5HTP抑制白细胞募集、AHR和相关抗原诱导的焦虑升高的假设。预期这些目标将确定以下方面的机制