Protein tryrosine phosphatase and glucocorticoids as modulators of mast cell action

蛋白酪氨酸磷酸酶在免疫功能中起重要作用。它们使质膜发出的信号去磷酸化和去磷酸化，以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被蛋白酪氨酸磷酸酶（PTP）灭活。由于几种PTP受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而发生的。然而，糖皮质激素的长期应用与几种不良反应有关，需要更好地了解其作用机制，以开发过敏的替代治疗策略。本工作的目的是使用基因敲除小鼠模型和生物化学和分子生物学技术，以确定是否糖皮质激素介导的调节PTP有助于抗过敏反应。我们将进一步发展我们以前的发现，PEST结构域富集酪氨酸磷酸酶（PEP），糖皮质激素上调的PTP之一，是过敏反应的正调节剂。我们将建立在这个重要的发现，以确定PEP在肥大细胞中的作用机制，并表征一系列新的PEP化学探针，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。

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.