The Function of Dual Specificity Phosphatase-5 in Immune Response

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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.