MKP-2 as an Endogenous Regulator of the Pro-Inflammatory Response in Sepsis

MKP-2 作为脓毒症促炎症反应的内源性调节剂

• 批准号: 8442334
• 负责人: TIMOTHY T CORNELL
• 金额: $ 12.63万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442334
• 关键词: 3CH134 protein; Affect; Age; Anti-Inflammatory Agents; Anti-inflammatory; Area; Attenuated; Binding; Biology; Bone Marrow; Cell Nucleus; Cell surface; Cessation of life; Chemicals; Childhood; Complex; Data; Development; Disease; Endotoxins; Environment; Enzymes; Equilibrium; Extracellular Signal Regulated Kinases; Family; Foundations; Functional disorder; Gene Expression; Genetic Transcription; Goals; Immune response; Immunology; Incidence; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Intraperitoneal Injections; Kinetics; Lead; Ligation; Lipopolysaccharides; MAPK8 gene; Mediating; Medicine; Mentors; Mentorship; Michigan; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Organ; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physicians; Process; Production; Protein Dephosphorylation; Protein Kinase; Proteins; Public Health; Puncture procedure; Regulation; Research; Role; Scientist; Sepsis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Sterility; System; Testing; Toll-Like Receptor 2; Toll-like receptors; Transcriptional Activation; Translations; Universities; Weight; Wild Type Mouse; arm; base; career; career development; chemokine; chromatin immunoprecipitation; cost; cytokine; expression vector; human MAPK14 protein; improved; inhibitor/antagonist; insight; macrophage; mortality; new therapeutic target; novel; novel therapeutics; pathogen; programs; promoter; public health relevance; receptor; response; sex

DESCRIPTION (provided by applicant): Severe sepsis has a significant impact on public health with an estimated incidence of nearly 800,000 cases per year, resulting in over 200,000 deaths and an annual cost of over $17 billion. The pathophysiology of sepsis involves a dysregulation of the inflammatory response leading to an imbalance between pro-inflammatory and anti-inflammatory mediators resulting from the complex interactions of signal transduction pathways. A more comprehensive understanding of the regulation of the signal transduction pathways involved is necessary to identify novel therapeutic targets. The Mitogen Activated Protein Kinase pathway (MAPK), a primary signal transduction pathway involved in sepsis, is comprised of cascades of kinases that when activated ultimately lead to the production of inflammatory cytokines. The dual-specific phosphatases are a family of enzymes that dephosphylorate and deactivate the kinases of the MAPK pathway. The prototypical dual-specific phosphatase, MAP kinase phosphatase-1 (MKP-1), has been shown to be a negative regulator of the pro- inflammatory response. However, the regulatory role of MKP-2, a phosphatase closely related to MKP-1, in sepsis has not been studied. Our preliminary data show improved survival and decreased pro-inflammatory cytokine expression following intraperitoneal injection of lipopolysaccharide (LPS) in mice lacking MKP-2 expression. The objectives of this proposal are first to elucidate the role of MKP-2 in modulating pro-inflammatory gene expression and organ injury triggered by experimental sepsis and second to provide a mentored environment for the PI to establish a foundation upon which to build an independent research career as a Physician-Scientist. The central hypothesis is that MKP-2 is induced and positively regulates pro-inflammatory pathways activated during the course of sepsis. The specific aims of this proposal are I) to investigate the regulatory control of MKP-2 induction following Toll-Like Receptor (TLR) stimulation, II) to study the regulatory effects of MKP-2 on the ERK, JNK and p38 MAPK pathways involved in sepsis-induced cytokine/chemokine gene expression and III) to determine the effects of MKP-2 deletion on cytokine expression, organ injury and pathogen clearance using established models of sepsis. These aims will be investigated by the PI under the mentorship of Dr. Steven Kunkel and co-mentorship of Dr. Thomas Shanley in the Immunology program at the University of Michigan.

描述（由申请人提供）：严重败血症对公共卫生有重大影响，估计每年发生近80万例，导致20多万人死亡，每年的费用超过170亿美元。脓毒症的病理生理涉及炎症反应的失调，导致促炎和抗炎介质之间的不平衡，这是由信号转导途径的复杂相互作用引起的。更全面地了解所涉及的信号转导通路的调节对于确定新的治疗靶点是必要的。丝裂原活化蛋白激酶途径（MAPK）是脓毒症的主要信号转导途径，由激酶级联组成，当激活时最终导致炎症细胞因子的产生。双特异性磷酸酶是一个家族的酶去磷和失活的激酶的MAPK途径。典型的双特异性磷酸酶，MAP激酶磷酸酶-1 (MKP-1)，已被证明是促炎反应的负调节因子。然而，与MKP-1密切相关的磷酸酶MKP-2在脓毒症中的调节作用尚未研究。我们的初步数据显示，在缺乏MKP-2表达的小鼠中，腹腔注射脂多糖（LPS）可以提高生存率，降低促炎细胞因子的表达。本提案的目的首先是阐明MKP-2在调节实验性败血症引发的促炎基因表达和器官损伤中的作用，其次是为PI提供一个指导环境，为其作为一名内科科学家建立独立研究生涯奠定基础。核心假设是MKP-2在脓毒症过程中被诱导并积极调节激活的促炎通路。本课题的具体目的是：1)研究toll样受体（TLR）刺激后对MKP-2诱导的调控；2)研究MKP-2对参与脓毒症诱导的细胞因子/趋化因子基因表达的ERK、JNK和p38 MAPK通路的调控作用；3)利用已建立的脓毒症模型，确定MKP-2缺失对细胞因子表达、器官损伤和病原体清除的影响。这些目标将由PI在密歇根大学免疫学项目的Steven Kunkel博士和Thomas Shanley博士的指导下进行研究。

项目成果

Integrated nanoplasmonic sensing for cellular functional immunoanalysis using human blood.

• DOI: 10.1021/nn406370u
• 发表时间: 2014-03-25
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Oh, Bo-Ram;Huang, Nien-Tsu;Chen, Weiqiang;Seo, Jung Hwan;Chen, Pengyu;Cornell, Timothy T.;Shanley, Thomas P.;Fu, Jianping;Kurabayashi, Katsuo
• 通讯作者: Kurabayashi, Katsuo

Profiling inflammatory responses with microfluidic immunoblotting.

• DOI: 10.1371/journal.pone.0081889
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chang HN;Leroueil PR;Selwa K;Gasper CJ;Tsuchida RE;Wang JJ;McHugh WM;Cornell TT;Baker JR Jr;Goonewardena SN
• 通讯作者: Goonewardena SN

Bedside ultrasound in pediatric critical care: a review.

儿科重症监护中的床旁超声：综述。

• DOI: 10.1097/pcc.0b013e318223147e
• 发表时间: 2011
• 期刊: Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies
• 作者: Srinivasan,Sushant;Cornell,TimothyT
• 通讯作者: Cornell,TimothyT