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Protein tryrosine phosphatase and glucocorticoids as modulators of mast cell action

蛋白质酪氨酸磷酸酶和糖皮质激素作为肥大细胞作用的调节剂

基本信息

批准号：
124046702
负责人：
Professor Dr. Andrew C.B. Cato
金额：
--
依托单位：
Institut für Toxikologie und Genetik (ITG) (aufgelöst)
依托单位国家：
德国
项目类别：
Priority Programmes
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2016-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/124046702?language=en
关键词：
Protein tryrosine phosphatase glucocorticoids modulators

项目摘要

Protein tyrosine phosphatases play important role in immune function. They dephosphorylate and inactivate signals emanating from the plasma membrane to influence different processes within cells. In allergic reactions, signals triggered at the surface of mast cells are also inactivated by protein tyrosine phosphatases (PTP). As several PTPs are transcriptionally regulated by glucocorticoids, it is thought that the anti-allergic effects of glucocorticoids occur through the regulation of expression of these genes. The long-term application of glucocorticoid is however associated with several adverse reactions, requiring a better understanding of its mode of action for the development of alternative therapeutic strategies for allergy. The aim of this work is to use knock-out mouse models and biochemical and molecular biological techniques to determine whether glucocorticoid-mediated regulation of PTPs contribute to anti-allergic reactions. We will further develop our previously finding that PEST-domain-enriched tyrosine phosphatase (PEP), one of the PTPs upregulated by glucocorticoids, is a positive regulator of anaphylaxis. We will build upon this important finding to identify the mechanism of action of PEP in mast cells and to characterize a series of novel chemical probes of PEP that together with glucocorticoids could serve as potent inhibitors of mouse and human mast cell action. It is hoped that these studies will greatly increase our understanding on activation mechanisms in mast cells and will pave the way to the search for more effective compounds for anti-allergic therapy.

蛋白酪氨酸磷酸酶在免疫功能中发挥重要作用。它们使质膜发出的信号去磷酸化和失活，从而影响细胞内的不同过程。在过敏反应中，肥大细胞表面触发的信号也会被蛋白酪氨酸磷酸酶 (PTP) 灭活。由于多种 PTP 受到糖皮质激素的转录调节，因此认为糖皮质激素的抗过敏作用是通过调节这些基因的表达来实现的。然而，长期应用糖皮质激素会引起多种不良反应，需要更好地了解其作用方式，以开发过敏的替代治疗策略。这项工作的目的是利用基因敲除小鼠模型以及生化和分子生物学技术来确定糖皮质激素介导的 PTP 调节是否有助于抗过敏反应。我们将进一步发展我们之前的发现，即富含 PEST 结构域的酪氨酸磷酸酶 (PEP) 是糖皮质激素上调的 PTP 之一，是过敏反应的正调节因子。我们将在此重要发现的基础上确定 PEP 在肥大细胞中的作用机制，并表征一系列新型 PEP 化学探针，这些探针与糖皮质激素一起可以作为小鼠和人类肥大细胞作用的有效抑制剂。希望这些研究将大大增加我们对肥大细胞激活机制的理解，并为寻找更有效的抗过敏治疗化合物铺平道路。