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: 8239920
• 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/8239920
• 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. PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is that these studies are likely to provide important and novel insight as to the role of MKP-2 in the regulation of signal transduction pathways involved sepsis. Such an understanding will aid in the development of novel therapeutic strategies for patients with sepsis reducing the morbidity and mortality associated with the disease. This project will also provide career development for a Pediatric Intensivist increasing the critically low number of Physician- Scientists in the area of Pediatric Critical Medicine.

描述(申请人提供)：严重败血症对公众健康有重大影响，估计每年的发病率接近80万例，导致超过20万人死亡，每年的费用超过170亿美元。脓毒症的病理生理学涉及炎症反应的失调，导致促炎症和抗炎介质之间的失衡，这是由于信号转导通路的复杂相互作用造成的。为了确定新的治疗靶点，有必要更全面地了解所涉及的信号转导通路的调节。丝裂原活化蛋白激酶通路(MAPK)是参与脓毒症的主要信号转导通路，由一连串的激活酶组成，激活后最终导致炎性细胞因子的产生。双特异性磷酸酶是一个酶家族，负责去磷酰化和失活MAPK途径的激酶。典型的双特异性磷酸酶，MAP-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被研究。我们的初步数据显示，在MKP-2表达缺失的小鼠中，腹腔注射脂多糖(LPS)可提高小鼠的存活率，减少促炎细胞因子的表达。这项建议的目的首先是阐明MKP-2在调节实验性脓毒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，以建立作为医生-科学家的独立研究生涯的基础。中心假说是，MKP-2被诱导并积极调节在脓毒症过程中激活的促炎通路。本研究的具体目的是：1)研究Toll样受体(TLR)刺激后MKP-2诱导的调控；2)研究MKP-2对脓毒症诱导的细胞因子/趋化因子基因表达所涉及的ERK、JNK和p38 MAPK通路的调节作用；3)利用已建立的脓毒症模型，研究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在史蒂文·昆克尔博士的指导下进行调查，并在密歇根大学免疫学项目的托马斯·香利博士的共同指导下进行。 公共卫生相关性：该项目与公共卫生的相关性在于，这些研究可能为MKP-2在脓毒症信号转导通路调控中的作用提供重要而新颖的见解。这样的理解将有助于为脓毒症患者开发新的治疗策略，降低与该疾病相关的发病率和死亡率。该项目还将为一名儿科重症医生提供职业发展，增加儿科危重医学领域极少的内科科学家人数。