Resolution of inflammation in healing myocardial infarcts

缓解心肌梗塞中的炎症

基本信息

项目摘要

DESCRIPTION (provided by applicant): Effective repair of the infarcted heart depends on mechanisms that suppress the inflammatory response after granulation tissue formation has occurred, and that limit expansion of fibrosis to the non-infarcted myocardium. Our project examines the mechanisms responsible for resolution of post-infarction inflammation and transition to fibrous tissue deposition. Our preliminary experiments suggest that Thrombospondin (TSP)-1, a potent angiostatic mediator and crucial TGF-2 activator, and the matrix crosslinking enzyme tissue transglutaminase (tTG), are selectively induced in the infarct border zone and that TSP-1 plays a key role in suppression of the chemokine response and resolution of the inflammatory infiltrate in healing infarcts. The selective localization of TSP-1 and tTG suggests that, through its unique composition, the infarct border zone may serve as a barrier preventing expansion of granulation tissue formation into the non- infarcted myocardium. Specific aim 1 will examine the role of TSP-1 in suppression and containment of the post-infarction inflammatory response. In vivo experiments examining activation of TGF-2 signaling pathways and neovessel formation, in vitro studies using endothelial cells and infarct myofibroblasts isolated from TSP-1 -/- and WT mice and injections of peptides that restore specific actions of the TSP-1 molecule will be used to examine the mechanistic basis of the TSP-1-mediated effects. Specific aim 2 will test the hypothesis that tTG may protect the non-infarcted myocardium by locally activating TGF- beta and by forming a "barrier" composed of proteolysis-resistant matrix, preventing leukocyte migration. In vivo studies using tTG -/- mice and in vitro experiments using infarct myofibroblasts and endothelial cells from WT and tTG -/- mice will be performed. Specific aim 3 will explore the signaling pathways responsible for the distinct effects of TGF-2 in suppressing inflammation by repressing chemokine and cytokine expression in endothelial cells, and in promoting fibrosis, by inducing extracellular matrix proteins and by altering the MMP:TIMP balance in cardiac fibroblasts. The importance of Smad- dependent and Smad-independent pathways in post-infarction inflammation and fibrous tissue deposition will be examined using myocardial infarction experiments and in vitro studies on isolated endothelial cells and fibroblasts. These studies may lead to therapeutic interventions aimed at optimizing cardiac repair by preventing prolongation and extension of the inflammatory injury.
描述(由申请人提供):梗死心脏的有效修复依赖于抑制肉芽组织形成后的炎症反应的机制,并限制纤维化向非梗死心肌的扩展。我们的项目研究了梗死后炎症和向纤维组织沉积过渡的机制。我们的初步实验表明,血栓反应蛋白(TSP)-1,一种有效的血管抑制介质和关键的TGF-2激活剂,以及基质交联酶组织转谷氨酰胺酶(tTG),在梗死边界区被选择性诱导,TSP-1在抑制趋化因子反应和愈合梗死中炎症浸润的解决中起关键作用。TSP-1和tTG的选择性定位表明,通过其独特的成分,梗死边界区可能作为阻止肉芽组织扩张到非梗死心肌的屏障。具体目的1将检查TSP-1在梗死后炎症反应的抑制和遏制中的作用。体内实验检查TGF-2信号通路的激活和新血管形成,体外研究使用从TSP-1- /-和WT小鼠中分离的内皮细胞和梗死肌成纤维细胞,以及注射恢复TSP-1分子特异性作用的肽,将用于检查TSP-1介导作用的机制基础。特异性目的2将验证tTG可能通过局部激活TGF- β,形成由抗蛋白水解基质组成的“屏障”,阻止白细胞迁移,从而保护非梗死心肌的假设。将使用tTG -/-小鼠进行体内研究,并使用WT和tTG -/-小鼠的梗死肌成纤维细胞和内皮细胞进行体外实验。特异性目标3将探索TGF-2通过抑制内皮细胞中的趋化因子和细胞因子表达来抑制炎症、通过诱导细胞外基质蛋白和改变心脏成纤维细胞中MMP:TIMP平衡来促进纤维化的独特作用的信号通路。Smad依赖性和非依赖性通路在梗死后炎症和纤维组织沉积中的重要性将通过心肌梗死实验和分离内皮细胞和成纤维细胞的体外研究来检验。这些研究可能会导致旨在通过防止炎症损伤的延长和扩展来优化心脏修复的治疗干预。

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 }}

Nikolaos G Frangogiannis其他文献

1168-164 Relation of diastolic strain measurements by Doppler echocardiography to myocardial structure and function in healing canine infarcts: Implications for the assessment of myocardial viability
  • DOI:
    10.1016/s0735-1097(04)91544-6
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Tae-Ho Park;Sherif F Nagueh;Dirar S Khoury;Helen A Kopelen;Spyridon Akrivakis;Kamal Nasser;Guofeng Ren;Nikolaos G Frangogiannis
  • 通讯作者:
    Nikolaos G Frangogiannis

Nikolaos G Frangogiannis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('Nikolaos G Frangogiannis', 18)}}的其他基金

Regulation of the TGF-beta superfamily in the remodeling and failing heart
TGF-β超家族在心脏重塑和衰竭中的调节
  • 批准号:
    10360502
  • 财政年份:
    2020
  • 资助金额:
    $ 36.98万
  • 项目类别:
Regulation of the TGF-beta superfamily in the remodeling and failing heart
TGF-β超家族在心脏重塑和衰竭中的调节
  • 批准号:
    10591491
  • 财政年份:
    2020
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    10543996
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    7556351
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    7365283
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of Inflammation in healing Myocardial Infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    8682984
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of Inflammation in healing Myocardial Infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    8437449
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts.
治愈心肌梗塞过程中炎症的消退。
  • 批准号:
    10814032
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    7748916
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Resolution of inflammation in healing myocardial infarcts
缓解心肌梗塞中的炎症
  • 批准号:
    8011082
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:

相似海外基金

Development of Novel Lung Cancer Therapy Using Tumor-Specific Angiogenesis Inhibitors and Drug Repositioning
使用肿瘤特异性血管生成抑制剂和药物重新定位开发新型肺癌疗法
  • 批准号:
    21H03019
  • 财政年份:
    2021
  • 资助金额:
    $ 36.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Development of biomarkers related to drug resistance of angiogenesis inhibitors
血管生成抑制剂耐药性相关生物标志物的开发
  • 批准号:
    20K08542
  • 财政年份:
    2020
  • 资助金额:
    $ 36.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural and Functional Studies of Brain Angiogenesis Inhibitors (BAIs/ADGRBs)
脑血管生成抑制剂 (BAIs/ADGRB) 的结构和功能研究
  • 批准号:
    9813883
  • 财政年份:
    2019
  • 资助金额:
    $ 36.98万
  • 项目类别:
Elucidation of proteinuria expression mechanism by angiogenesis inhibitors and research on adverse effect avoidance
血管生成抑制剂蛋白尿表达机制的阐明及不良反应避免的研究
  • 批准号:
    17K08457
  • 财政年份:
    2017
  • 资助金额:
    $ 36.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Evaluation of cardiotoxicity and elucidation of cardiotoxic molecular mechanisms in cancer patients receiving angiogenesis inhibitors
接受血管生成抑制剂的癌症患者的心脏毒性评估和心脏毒性分子机制的阐明
  • 批准号:
    26461102
  • 财政年份:
    2014
  • 资助金额:
    $ 36.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Minimally invasive response evaluation in vivo for the dual therapy of the angiogenesis inhibitors
血管生成抑制剂双重治疗的体内微创疗效评价
  • 批准号:
    23591763
  • 财政年份:
    2011
  • 资助金额:
    $ 36.98万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
ANGIOGENESIS INHIBITORS IN THE MULTIMODAL TREATMENT OF PEDIATRIC SOLID TUMORS
血管生成抑制剂在小儿实体瘤多模式治疗中的应用
  • 批准号:
    8309814
  • 财政年份:
    2011
  • 资助金额:
    $ 36.98万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    7351352
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Discovery and Investigation of Novel Angiogenesis Inhibitors Among Existing Drugs
现有药物中新型血管生成抑制剂的发现和研究
  • 批准号:
    8002099
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
Novel Angiogenesis Inhibitors Targeting the Anthrax Toxin Receptors
针对炭疽毒素受体的新型血管生成抑制剂
  • 批准号:
    7615664
  • 财政年份:
    2008
  • 资助金额:
    $ 36.98万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了