The Function of Dual Specificity Phosphatase-5 in Immune Response

双特异性磷酸酶 5 在免疫反应中的作用

• 批准号: 7642279
• 负责人: Yusen Liu
• 金额: $ 18.89万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642279
• 关键词: Alleles; Applications Grants; Attenuated; Bacteria; Biochemical; Cell Nucleus; Cell membrane; Cells; Congenital Abnormality; Craniosynostosis; DUSP1 gene; Development; Disease; Dwarfism; Embryo; Exhibits; Exons; Extracellular Signal Regulated Kinases; Family; Genes; Genetic Transcription; Growth Factor; Hand; Human Development; Immediate-Early Genes; Immune; Immune response; Immunity; In Vitro; Individual; Inflammatory; Inflammatory Response; Interleukin-2; Investigation; Knock-out; Knockout Mice; Lead; Ligands; MAP kinase phosphatase MKP-5; MAPK14 gene; MAPK8 gene; MEKs; Mediating; Mitogen-Activated Protein Kinases; Molecular Abnormality; Mus; Neonatal; Nuclear; PAC1 phosphatase; PP5 protein-serine-threonine phosphatase; Pathway interactions; Pattern; Phenotype; Phosphoric Monoester Hydrolases; Phosphothreonine; Phosphotyrosine; Physiological; Placenta; Play; Predisposition; Production; Protein Dephosphorylation; Protein phosphatase; Receptor Activation; Regulation; Role; Septic Shock; Signal Pathway; Site; Specificity; Stimulus; Stress; T-Cell Proliferation; T-Cell Receptor; Testing; Toll-like receptors; Transcript; base; cytokine; extracellular; fetal; hearing impairment; human disease; inorganic phosphate; insight; macrophage; mammalian genome; member; novel; novel diagnostics; postnatal; preference; public health relevance; response; skeletal; therapeutic target; tool; transcription factor

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.

描述（由申请人提供）：双特异性蛋白磷酸酶（DUSP）5是促分裂原活化蛋白激酶（MAPK）磷酸酶（MKP）家族的成员，其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抑制MAPK。尽管生物化学研究强烈支持DUSP 5作为ERK特异性磷酸酶的观点，但DUSP 5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在免疫应答的调节中发挥重要和多样化的作用。此外，至少两个MKP在正常发育中起重要作用。为了理解DUSP 5的生理功能，我们已经产生了携带Dusp 5等位基因的小鼠，其中外显子3两侧是两个loxP位点。这些小鼠可以方便地用于产生组成型和条件性Dusp 5敲除小鼠。本申请中的研究将检查DUSP 5在发育中的作用，并研究DUSP 5在先天性和适应性免疫应答中的生理功能。具体目标是：1）研究Dusp 5是否是正常发育所必需的; 2）测试Dusp 5的敲除将增强ERK途径并使先天性免疫应答偏斜，导致细胞因子产生改变的假设;和3）测试DUSP 5响应于T细胞受体活化而减弱IL-2表达和T细胞增殖的假设。完成拟议的研究将揭示DUSP 5在调节免疫反应中的作用。这些研究可能潜在地揭示用于治疗许多炎性疾病的新型调控网络。这项研究还将回答Dusp 5是否是ERK通路的生理调节剂以及它是否在正常发育中起重要作用的问题。 公共卫生相关性异常的免疫反应是导致人类多种疾病的主要原因。基因异常导致人类发育异常，是许多出生缺陷和新生儿疾病的根源。在这项资助申请中，我们建议研究DUSP 5在正常胎儿/新生儿发育和免疫反应中的作用。拟议的研究可能会发现独特的调控网络，并导致新的诊断工具和治疗靶点。