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IL-18 Signaling in Mesenchymal Stem Cells: Function and Surgial Protection

间充质干细胞中的 IL-18 信号传导：功能和手术保护

基本信息

批准号：
7672490
负责人：
Aaron Abarbanell
金额：
$ 5.26万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7672490
关键词：
Acute Graft Versus Host Disease Address Affect Angiogenesis Inhibitors Animal Model Apoptosis Bone Marrow Bone Marrow Stem Cell Cardiac Cardiovascular Diseases Cell Proliferation Cell physiology Cessation of life FGF2 gene Genetic Growth Factor Heart Heart Diseases Heart failure Hospitalization Immune response Infarction Inflammation Insulin-Like Growth Factor I Interleukin-1 Interleukin-18 Ischemia MAP Kinase Gene MAPK14 gene Mediating Mesenchymal Stem Cells Modality Modification Myocardial Myocardial Ischemia Play Production Proteins Public Health Reperfusion Therapy Reporting Research Role Signal Transduction Small Interfering RNA Stem cell transplant Stem cells TNF gene Therapeutic Tissues Vascular Endothelial Growth Factors Wound Healing cytokine improved functioning injured interleukin-18 binding protein member novel paracrine preconditioning

项目摘要

DESCRIPTION (provided by applicant): Myocardial ischemia and subsequent heart failure are leading causes of hospitalization and death. Stem cells are a promising treatment modality for injured cardiac tissue and may mediate their beneficial cardiac effects in part by paracrine mechanisms. Stem cell treatment of injured cardiac tissue may reduce inflammation, apoptosis, infarct size and improve function via factors that promote tissue repair. This paracrine protection may be enhanced by ex vivo modification. Genetic modification, VEGF transduction, and even preconditioning have been shown to enhance stem cell paracrine cardioprotection in animal models. Interestingly, we have recently shown that modulation of cytokines may enhance protective growth factor production. IL-18, a novel member of the IL-1 cytokine superfamily, is now recognized as an important regulator of innate and acquired immune responses. Recent research indicates that IL-18 may play an important role in acute graft versus host disease after stem cell transplantation. IL-18 has also been reported to play an antiangiogenic role in bone marrow derived endothelial progenitor cells. However, the effect of IL-18 on bone marrow mesenchymal stem cell (MSC) production of growth factors remains unknown. Thus, it is important to delineate the effects of IL-18 signaling in stem cell activation in order to further understand the role of stem cells in cardiac disease and maximize stem cell protective factors during therapeutic myocardial protection. We hypothesize that: 1) IL-18 will decrease MSC production of growth factors through p38 MARK, ERK or Akt signals; 2) IL-18 binding protein may neutralize the negative effects of IL-18 on MSC release of growth factors and enhance MSC cardioprotection during ischemia and reperfusion (I/R). To address these hypotheses we propose the following four specific aims: 1. To determine whether IL-18 signaling affects activated mesenchymal stem cell production of VEGF, HGF, IGF-1 and the cytokine TNF, and if so, whether this effect is mediated by p38 MARK, ERK, or Akt signaling. 2. To determine whether IL-18 binding protein may neutralize the effect of IL-18 on MSC release of VEGF, HGF, IGF-1 and the cytokine TNF. 3. To elucidate whether IL-18 signaling affects mesenchymal stem cell proliferation and apoptosis, and if so, whether targeted knockdown of VEGF or HGF expression by siRNA may neutralize these effects. 4. To determine whether MSC myocardial protection during I/R may be enhanced by IL-18 binding protein. PUBLIC HEALTH IN LAY TERMS: Bone marrow stem cells may be useful to fix injured hearts. We aim to study a protein called IL-18 so that we can utilize the ability of stem cells to protect the heart.

描述（由申请人提供）：心肌缺血和随后的心力衰竭是住院和死亡的主要原因。干细胞是一种很有前途的治疗心脏组织损伤的方式，可能部分通过旁分泌机制介导其有益心脏的作用。干细胞治疗损伤的心脏组织可以减少炎症、细胞凋亡、梗死面积，并通过促进组织修复的因素改善功能。这种旁分泌保护可以通过体外修饰来增强。在动物模型中，基因修饰、VEGF转导，甚至预处理都被证明可以增强干细胞旁分泌心脏保护作用。有趣的是，我们最近发现细胞因子的调节可以增强保护性生长因子的产生。IL-18是IL-1细胞因子超家族的新成员，目前被认为是先天和获得性免疫反应的重要调节因子。最近的研究表明，IL-18可能在干细胞移植后的急性移植物抗宿主病中发挥重要作用。IL-18也被报道在骨髓来源的内皮祖细胞中发挥抗血管生成作用。然而，IL-18对骨髓间充质干细胞（MSC）生成生长因子的影响尚不清楚。因此，阐明IL-18信号在干细胞活化中的作用，对于进一步了解干细胞在心脏病中的作用，并在治疗性心肌保护中最大限度地发挥干细胞保护因子的作用具有重要意义。我们假设：1)IL-18通过p38 MARK、ERK或Akt信号减少MSC生长因子的产生；2) IL-18结合蛋白可以中和IL-18对骨髓间充质干细胞释放生长因子的负面影响，增强骨髓间充质干细胞缺血再灌注（I/R）时的心脏保护作用。为了解决这些假设，我们提出以下四个具体目标：1。确定IL-18信号是否影响活化的间充质干细胞产生VEGF、HGF、IGF-1和细胞因子TNF，如果有，这种影响是否由p38 MARK、ERK或Akt信号介导。2. 确定IL-18结合蛋白是否可以中和IL-18对MSC释放VEGF、HGF、IGF-1及细胞因子TNF的影响。3. 为了阐明IL-18信号是否影响间充质干细胞的增殖和凋亡，如果是，是否通过siRNA靶向抑制VEGF或HGF的表达可以中和这些影响。4. 目的探讨IL-18结合蛋白是否能增强骨髓间充质干细胞在I/R期间的心肌保护作用。通俗的公共卫生术语：骨髓干细胞可能对修复受伤的心脏有用。我们的目标是研究一种叫做IL-18的蛋白质，这样我们就可以利用干细胞的能力来保护心脏。