The Function of Dual Specificity Phosphatase-5 in Immune Response

描述（由申请人提供）：双特异性蛋白磷酸酶（DUSP） 5是丝裂原活化蛋白激酶（MAPK）磷酸酶（MKPs）家族的成员，它可以通过从磷酸苏氨酸和磷酸酪氨酸残基中去除磷酸盐来灭活MAPK。尽管生化研究强烈支持DUSP5作为erk特异性磷酸酶的观点，但DUSP5的生理功能仍然难以捉摸。最近对MKP家族的研究提供了令人信服的证据，表明个体MKP在免疫反应的调节中发挥着重要而多样的作用。此外，至少有两种MKPs在正常发育中起重要作用。为了了解DUSP5的生理功能，我们产生了携带DUSP5等位基因的小鼠，其中外显子3两侧有两个loxP位点。这些小鼠可以方便地用于创建构成型和条件性Dusp5敲除小鼠。本研究将研究DUSP5在发育中的作用，并研究DUSP5在先天和适应性免疫反应中的生理功能。具体目的是：1)研究Dusp5是否为正常发育所必需；2)验证敲除Dusp5会增强ERK通路，扭曲先天免疫反应，导致细胞因子产生改变的假设；3)验证DUSP5在T细胞受体激活的情况下降低IL-2表达和T细胞增殖的假设。拟议研究的完成将揭示DUSP5在调节免疫反应中的作用。这些研究可能潜在地揭示许多炎症性疾病治疗的新调控网络。这条研究路线也将回答Dusp5是否是ERK通路的生理调节因子以及它是否在正常发育中起重要作用的问题。

DESCRIPTION (provided by applicant): Dual specificity protein phosphatase (DUSP) 5 is a member of the mitogen-activated protein kinase (MAPK) phosphatases (MKPs) family, which can inactivate MAPKs by removing the phosphates from both the phosphothreonine and phosphotyrosine residues. Although biochemical studies have strongly supported the notion that DUSP5 acts as an ERK-specific phosphatase, the physiological function of DUSP5 remains elusive. Recent studies on the MKP family have provided compelling evidence that the individual MKPs play important and diverse roles in the regulation of immune responses. Furthermore, at least two MKPs, play an important role in normal development. To understand the physiological functions of DUSP5, we have generated mice carrying a Dusp5 allele where exon 3 is flanked by two loxP sites. These mice can be conveniently used to create constitutive and conditional Dusp5 knockout mice. The studies in this application will examine the role of DUSP5 in development and investigate the physiological function of DUSP5 in both innate and adaptive immune responses. The Specific Aims are: 1) To investigate whether Dusp5 is essential for normal development; 2) To test the hypothesis that knockout of Dusp5 will potentiate the ERK pathway and skew innate immune responses, resulting in alterations in cytokine production; and 3) To test the hypothesis that DUSP5 serves to attenuate IL-2 expression and T cell proliferation in response to T cell receptor activation. Completion of the proposed studies will reveal the role of DUSP5 in the regulation of immune responses. These studies may potentially unravel novel regulatory networks for the treatment of many inflammatory diseases. This line of investigation will also answer the questions whether Dusp5 is a physiological regulator of the ERK pathway and whether it plays an essential role in normal development. PUBLIC HEALTH RELEVANCE Abnormal immune responses are a major cause of a vast array of human diseases. Genetic abnormalities giving rise to aberrant human development underlie many birth defects and neonatal diseases. In this grant application we propose to study the role of DUSP5 in both normal fetal/neonatal development and immune responses. The proposed studies may uncover unique regulatory networks and lead to novel diagnostic tools and therapeutic targets.