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

基本信息

  • 批准号:
    7894084
  • 负责人:
  • 金额:
    $ 12.63万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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(由申请人提供):严重脓毒症对公共卫生有重大影响,估计每年发生近80万例病例,导致超过20万例死亡,每年花费超过170亿美元。脓毒症的病理生理学涉及炎症反应的失调,导致由信号转导途径的复杂相互作用引起的促炎和抗炎介质之间的失衡。更全面地了解所涉及的信号转导通路的调节是必要的,以确定新的治疗靶点。有丝分裂原活化蛋白激酶途径(MAPK)是脓毒症中涉及的主要信号转导途径,其由激酶级联组成,所述激酶级联在被活化时最终导致炎性细胞因子的产生。双特异性磷酸酶是使MAPK途径的激酶去磷酸化和失活的酶家族。原型双特异性磷酸酶,MAP激酶磷酸酶-1(MKP-1)已被证明是促炎反应的负调节剂。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表达的小鼠中腹膜内注射脂多糖(LPS)后,存活率提高,促炎细胞因子表达降低。 本提案的目的首先是阐明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。中心假设是,MKP-2是诱导的,并积极调节脓毒症过程中激活的促炎途径。本提案的具体目的是:I)研究Toll样受体(TLR)刺激后MKP-2诱导的调控,II)研究MKP-2对脓毒症诱导的细胞因子/趋化因子基因表达中涉及的ERK、JNK和p38 MAPK通路的调控作用,III)确定MKP-2缺失对细胞因子表达的影响,器官损伤和病原体清除。这些目标将由PI在Steven Kunkel博士的指导下和托马斯尚利博士在密歇根大学免疫学项目的共同指导下进行研究。 公共卫生关系:该项目与公共卫生的相关性在于,这些研究可能为MKP-2在脓毒症相关信号转导通路调节中的作用提供重要和新颖的见解。这样的理解将有助于发展新的治疗策略,脓毒症患者减少与疾病相关的发病率和死亡率。该项目还将为儿科重症监护医师提供职业发展,增加儿科重症医学领域的医生科学家数量。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

TIMOTHY T CORNELL其他文献

TIMOTHY T CORNELL的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('TIMOTHY T CORNELL', 18)}}的其他基金

Microfluidic Functional Immunophenotyping of Pediatric Patients Following Cardiop
儿科患者心脏手术后的微流控功能免疫表型
  • 批准号:
    8694625
  • 财政年份:
    2014
  • 资助金额:
    $ 12.63万
  • 项目类别:
Microfluidic Functional Immunophenotyping of Pediatric Patients Following Cardiop
儿科患者心脏手术后的微流控功能免疫表型
  • 批准号:
    9066783
  • 财政年份:
    2014
  • 资助金额:
    $ 12.63万
  • 项目类别:
Microfluidic Functional Immunophenotyping of Pediatric Patients Following Cardiop
儿科患者心脏手术后的微流控功能免疫表型
  • 批准号:
    9273597
  • 财政年份:
    2014
  • 资助金额:
    $ 12.63万
  • 项目类别:
Microfluidic Functional Immunophenotyping of Pediatric Patients Following Cardiop
儿科患者心脏手术后的微流控功能免疫表型
  • 批准号:
    8894576
  • 财政年份:
    2014
  • 资助金额:
    $ 12.63万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 12.63万
  • 项目类别:
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
  • 财政年份:
    2010
  • 资助金额:
    $ 12.63万
  • 项目类别:
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:
    8055033
  • 财政年份:
    2010
  • 资助金额:
    $ 12.63万
  • 项目类别:

相似国自然基金

靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
  • 批准号:
    JCZRQN202500010
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
  • 批准号:
    2025JJ70209
  • 批准年份:
    2025
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
  • 批准号:
  • 批准年份:
    2024
  • 资助金额:
    0 万元
  • 项目类别:
    面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
  • 批准号:
    2023JJ50274
  • 批准年份:
    2023
  • 资助金额:
    0.0 万元
  • 项目类别:
    省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
  • 批准号:
  • 批准年份:
    2022
  • 资助金额:
    33 万元
  • 项目类别:
    地区科学基金项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
  • 批准号:
    n/a
  • 批准年份:
    2022
  • 资助金额:
    10.0 万元
  • 项目类别:
    省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 批准年份:
    2019
  • 资助金额:
    55.0 万元
  • 项目类别:
    面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
  • 批准号:
    81602908
  • 批准年份:
    2016
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
  • 批准号:
    81501928
  • 批准年份:
    2015
  • 资助金额:
    18.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
  • 批准号:
    2341426
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
  • 批准号:
    2341424
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Continuing Grant
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政​​策的情绪动态
  • 批准号:
    10108433
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
  • 批准号:
    MR/X032809/1
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
  • 批准号:
    MR/X034690/1
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Fellowship
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
  • 批准号:
    24K13490
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
  • 批准号:
    EP/Z00022X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
  • 批准号:
    MR/Y003365/1
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
  • 批准号:
    2335955
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
  • 批准号:
    AH/Y007549/1
  • 财政年份:
    2024
  • 资助金额:
    $ 12.63万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了