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是丝裂原激活蛋白激酶(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上去除磷酸来使MAPK失活。虽然生化研究强烈支持DUSP5作为ERK特异性磷酸酶的概念，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，表明单个MKP在免疫反应的调节中发挥着重要而多样的作用。此外，至少有两个MKP，在正常发展中发挥着重要作用。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结构性和条件性Dusp5基因敲除小鼠。本应用中的研究将检测DUSP5在发育中的作用，并研究DUSP5在先天性和获得性免疫反应中的生理功能。其具体目的是：1)研究Dusp5是否对正常发育是必要的；2)检验Dusp5基因敲除将增强ERK通路并扭曲先天免疫反应的假说，导致细胞因子产生的改变；3)检验DUSP5有助于减弱IL-2表达和T细胞增殖以响应T细胞受体激活的假说。拟议研究的完成将揭示DUSP5在免疫反应调节中的作用。这些研究可能会为治疗许多炎症性疾病揭开新的调控网络的面纱。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发挥重要作用。 公共卫生相关性免疫反应异常是导致人类多种疾病的主要原因。导致人类发育异常的基因异常是许多出生缺陷和新生儿疾病的基础。在这项拨款申请中，我们建议研究DUSP5在正常胎儿/新生儿发育和免疫反应中的作用。拟议的研究可能会揭示独特的调控网络，并导致新的诊断工具和治疗靶点。

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.