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

基本信息

  • 批准号:
    8577431
  • 负责人:
  • 金额:
    $ 36.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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):哮喘和过敏性疾病的患病率在过去40年中急剧增加。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,5-羟色氨酸(5 HTP)补充剂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,但许多报告表明,5 HTP和5-羟色胺给药对生理反应具有相反的结果。5 HTP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/哮喘相关,但这种相关性的机制尚不清楚。 也有报道称,在用过敏原攻击的啮齿动物中,焦虑增加,这表明潜在的协调调节。我们提出了一个新的概念,白细胞募集和焦虑/抑郁在过敏/哮喘协调减少5 HTP补充。 5 HTP被代谢成5-羟色胺,然后5-羟色胺结合抑制性或刺激性5-羟色胺受体(HTR)或5-羟色胺共价连接至蛋白质(羟色胺酰化)。 与我们的新概念一致,我们报道了5 HTP减少过敏性炎症,减少过敏原诱导的内皮细胞中的羟丙酰化,并减少过敏原诱导的AHR。在体外,5-羟色胺-预处理的内皮细胞阻断白细胞跨内皮迁移,并阻断姜黄素刺激的内皮细胞的乙酰化,表明负反馈调节5-羟色胺。 我们的长期目标是确定过敏/哮喘中5 HTP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。作为实现我们长期目标的一步,我们的中心假设是,容易获得的氨基酸补充剂5 HTP(来自植物Griffonia Simplicifolia)通过5 HTP抑制内皮细胞信号限制白细胞募集,从而抑制嗜酸性粒细胞依赖性AHR和过敏原诱导的焦虑。我们将测试我们的中心假设与以下具体目标:目标1。 检验内皮细胞和/或白细胞上的HTR介导5 HTP体外抑制白细胞跨内皮迁移的假设。目标二。检验在体外VCAM-1依赖性白细胞跨内皮迁移过程中5 HTP抑制内皮细胞中VCAM-1细胞内信号的假设。 目标3。检验以下假设:5 HTP通过5 HTP调节HTR或腺苷二酰化抑制白细胞募集、AHR和相关抗原诱导的焦虑升高。预计这些目标将确定以下机制: 5 HTP抑制过敏性炎症、过敏原诱导的AHR和焦虑。 这些结果预计将产生重要的积极影响,因为除了推进对5 HTP调节炎症的机制的理解之外,还可能确定新的干预靶点。

项目成果

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JOAN M COOK-MILLS其他文献

JOAN M COOK-MILLS的其他文献

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{{ truncateString('JOAN M COOK-MILLS', 18)}}的其他基金

Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10653024
  • 财政年份:
    2020
  • 资助金额:
    $ 36.77万
  • 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10032718
  • 财政年份:
    2020
  • 资助金额:
    $ 36.77万
  • 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10203801
  • 财政年份:
    2020
  • 资助金额:
    $ 36.77万
  • 项目类别:
Mechanisms for initiation of food allergy early in life
生命早期发生食物过敏的机制
  • 批准号:
    10441368
  • 财政年份:
    2020
  • 资助金额:
    $ 36.77万
  • 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
  • 批准号:
    9323656
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9981971
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9380183
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    10160774
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:
Lipid Regulation of the Development of Responsiveness to Allergen in Neonates and Infants
新生儿和婴儿对过敏原反应性发展的脂质调节
  • 批准号:
    9919537
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:
Tocopherol regulation of the development of responsiveness to allergen early in life
生育酚对生命早期过敏原反应性发展的调节
  • 批准号:
    9925738
  • 财政年份:
    2017
  • 资助金额:
    $ 36.77万
  • 项目类别:

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