P2X3 is a Female-Dominant Amplifier of Mast Cell Function

P2X3 是肥大细胞功能的女性主导放大器

基本信息

批准号：
10317599
负责人：
John J Ryan
金额：
$ 37万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10317599
关键词：
ATP Receptors Allergic Disease Allergic inflammation Amplifiers Antibodies Antidepressive Agents Asthma B-Lymphocytes Cations Cell physiology Cells Cellular biology Clinical Complement Data Disease Estrogens Extrinsic asthma Female Fluoxetine Human Hypersensitivity IgE In Vitro Incidence Intervention Knockout Mice MAP Kinase Gene Mediating Membrane Modeling Molecular Mus Natural Immunity P2X-receptor Pathology Pathway interactions Pharmaceutical Preparations Production Proteins Public Health Pyroglyphidae Role Sex Bias Signal Transduction Testing Therapeutic Woman allergic airway inflammation autocrine drug repurposing eosinophil in vivo inhibitor/antagonist male mast cell novel pain sensation pain signal patch clamp receptor release of sequestered calcium ion into cytoplasm response selective expression sex sexual dimorphism

ATP Receptors Allergic Disease Allergic inflammation Amplifiers Antibodies Antidepressive Agents Asthma B-Lymphocytes Cations Cell physiology Cells Cellular biology Clinical Complement Data Disease Estrogens Extrinsic asthma Female Fluoxetine Human Hypersensitivity IgE In Vitro Incidence Intervention Knockout Mice MAP Kinase Gene Mediating Membrane Modeling Molecular Mus Natural Immunity P2X-receptor Pathology Pathway interactions Pharmaceutical Preparations Production Proteins Public Health Pyroglyphidae Role Sex Bias Signal Transduction Testing Therapeutic Woman allergic airway inflammation autocrine drug repurposing eosinophil in vivo inhibitor/antagonist male mast cell novel pain sensation pain signal patch clamp receptor release of sequestered calcium ion into cytoplasm response selective expression sex sexual dimorphism

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项目摘要

Project Summary The rising incidence of allergic disease is a public health challenge needing novel interventions. While mast cell activation by IgE has a known role in disease pathology, fundamental aspects of mast cell biology remain unclear. There is a particular need to understand sex-specific effects. Mast cells from female mice have stronger IgE-induced responses, an observation complementing the greater incidence and acuity of allergic asthma among women. In an effort to repurpose drugs, we found that fluoxetine (Prozac) potently suppresses mast cell activation by IgE. These data were consistent in vitro, in vivo, and with human mast cells. However, fluoxetine effects were strikingly female-restricted. Our results indicate fluoxetine has an off-target effect on P2X3, an ATP-activated cationic channel most often associated with pain signaling. We find that mast cells rapidly release ATP in response to IgE signaling, suggesting P2X3 is triggered in an autocrine loop. P2X3 was readily detectable on female but not male mast cells and may explain why female mast cells have stronger IgE responses. Like fluoxetine, P2X3-selective inhibitors greatly suppressed mast cell responses to IgE or ATP. Inhibitors of other P2X proteins had no effect. Our study will test the hypothesis that IgE signaling elicits ATP release that activates P2X3 selectively in females, amplifying allergic inflammation. This pathway could offer an explanation and a clinical target for sexual dimorphism in allergic disease. We have three Specific Aims: Aim 1: We will test the hypothesis that P2X3 enhances mast cell function in females. Aim 2: We will test the hypothesis that fluoxetine acts by suppressing P2X3 function and expression. Aim 3: We will test the hypothesis that P2X3 is a fundamental part of allergic airway inflammation that can be targeted in females.

项目摘要过敏性疾病的发生率上升是需要新干预的公共卫生挑战。而桅杆 IgE细胞激活在疾病病理学中具有已知作用，肥大细胞生物学的基本方面仍然存在不清楚。特别需要了解性别特定的效果。雌性小鼠的肥大细胞具有更强的IgE诱导的响应，这种观察值补充了过敏性的更大发生率和敏锐度女性哮喘。为了重新利用药物，我们发现氟西汀（百忧解）有效抑制肥大细胞通过IgE激活。这些数据在体外，体内和人类肥大细胞是一致的。然而，氟西汀作用受到了极大的女性限制。我们的结果表明氟西汀对 P2X3是ATP激活的阳离子通道，通常与疼痛信号传导有关。我们发现肥大细胞响应IgE信号传导迅速释放ATP，这表明P2X3是在自分泌环中触发的。 P2X3是容易在雌性但无法检测到雄性肥大细胞上，并且可以解释为什么雌性肥大细胞具有更强的IgE 回答。像氟西汀一样，P2X3选择性抑制剂极大地抑制了对IgE或ATP的肥大细胞反应。其他P2X蛋白的抑制剂无效。我们的研究将检验IgE信号引起ATP的假设在女性中选择性激活P2X3的释放，扩大过敏性炎症。这条路可以提供过敏性疾病中性二态性的解释和临床目标。我们有三个具体的目标： AIM 1：我们将测试P2X3增强女性肥大细胞功能的假设。 AIM 2：我们将通过抑制P2X3功能和表达来检验氟西汀起作用的假设。 AIM 3：我们将检验以下假设：P2X3是过敏气道炎症的基本部分针对女性。