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Cytokine Driven Mechanisms of Vein Graft Failure

静脉移植失败的细胞因子驱动机制

基本信息

批准号：
7884683
负责人：
C KEITH OZAKI
金额：
$ 29.15万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7884683
关键词：
Aftercare Anti-Inflammatory Agents Anti-inflammatory Antibodies Arterial Occlusive Diseases Arthritis Attention Attenuated Autologous Biology Blood Vessels Bypass Cell Proliferation Cells Coronary Cytokine Signaling Dependovirus Development Disease Down-Regulation Environment Enzyme Inhibition Evidence based treatment Failure Future Hand Homologous Gene Hour Hyperplasia Infiltration Inflammation Inflammation Mediators Inflammatory Inflammatory Bowel Diseases Interleukin-1 Interleukin-10 Intervention Knockout Mice Knowledge Laboratories Leukocytes Link Lower Extremity Mediating Membrane Methods Mus Myofibroblast Natural History Operative Surgical Procedures Pathologic Pathology Pathway interactions Patients Poxviridae Process Production Receptor Signaling Research Research Personnel Research Training Rheumatoid Arthritis Role Sepsis Signal Pathway Signal Transduction System TNF gene TNF-alpha converting enzyme Testing Time Translating Tumor Necrosis Factor Receptor Veins Viral Work base body system cell motility cytokine cytokine therapy design exhaust graft failure human MPP1 protein improved in vivo in vivo Model inhibitor/antagonist insight knowledge base mRNA Expression programs protective effect receptor response skills transcriptional coactivator p75

项目摘要

Surgical vein bypass grafts fail principally due to development of neointimal hyperplasia, especially in the setting of low flow within the conduit. Inflammation stands as a pathologic feature of this process. While cytokines have been implicated in vein graft failure, the initiating factors and signaling mechanisms for their expression (as well as the biologic implications of these inflammatory mediators in vein wall adaptations) remain largely unknown. Prior studies by our group directly implicate the production of both the pro- inflammatory cytokine TNF-o_ and anti-inflammatory cytokine IL-10 in modulation of arterial wall adaptations to changes in wall shear. In recent work we demonstrated specific time and flow dependent cytokine signatures in the early arterialized vein graft. TNF-c_ expression is induced almost 200-fold within 24 hours in low flow grafts that subsequently develop robust intimal hyperplasia, while high flow promotes a delayed induction of IL-10 mRNA expression, which appears to protect against occlusive adaptations. This proposal moves forward by testing two linked mechanistic hypotheses: 1) Vein grafts develop neointimal hyperplasia by way of low wall shear induced pro-inflammatory cytokine driven mechanisms (soluble TNF-a signaling via the p55 receptor, leading to enhanced leukocyte mediated inflammation, and increased cell proliferation). Signaling pathways will be dissected by studying vein grafts in mice lacking soluble TNF-_, or the p55 or p75 receptor. Under differential flow environments, TNF- (_ signaling will be defined through inhibition by soluble receptors, adeno-associated virus (AAV)-delivered TNF receptor homologs, specific p55 or p75 TNF receptor antibodies, or TNF-o_ converting enzyme inhibition. 2) IL-10 production protects vein grafts from over exuberant occlusive wall adaptations via reduced inflammatory leukocyte infiltration, myofibroblast proliferation, and down-regulation of TNF- c¿production. Vein grafts from IL-10 knockout mice will be examined, as well as conduits after treatment with exogenous IL-10 (both pharmacologic and AAV vIL-10). Based on new knowledge and skills obtained during the applicant's research training, the fundamental design of this initial independent proposal is to transfer basic cytokine biology to vascular biology, and throu.qh new mechanistic insights, translate these findin.qs into strate.qies to improve vein (]raft durability.

手术静脉旁路移植失败主要是由于新生内膜增生的发展，特别是在在导管内设置低流量。炎症是这一过程的病理特征。而细胞因子与静脉移植失败有关，它们的启动因子和信号机制，表达（以及这些炎症介质在静脉壁适应中的生物学意义）但基本上仍不为人所知。我们小组先前的研究直接涉及亲- 炎性细胞因子TNF-α和抗炎性细胞因子IL-10在动脉壁适应性调节中作用壁面剪力的变化。在最近的工作中，我们证明了特定的时间和流量依赖性细胞因子，早期动脉化静脉移植物的特征。TNF-α表达在24小时内被诱导近200倍，低流量移植物随后发展为强烈的内膜增生，而高流量移植物促进延迟的内膜增生。诱导IL-10 mRNA表达，这似乎可以防止闭塞适应。该建议通过测试两个相关的机制假设向前推进：1）静脉移植物的发展通过低壁剪切诱导的促炎细胞因子驱动的新生内膜增生机制（通过p55受体的可溶性TNF-α信号传导，导致增强的白细胞介导的炎症和增加的细胞增殖）。将通过研究静脉来解剖信号通路在缺乏可溶性TNF-α或p55或p75受体的小鼠中移植。在差流环境下，TNF- （_信号传导将通过可溶性受体、腺相关病毒（AAV）递送的抑制来定义。 TNF受体同源物、特异性p55或p75 TNF受体抗体或TNF-α转化酶抑制作用2)IL-10的产生通过以下途径保护静脉移植物免受过度的闭塞性壁适应减少炎性白细胞浸润、肌成纤维细胞增殖和TNF-α下调。 c生产。将检查来自IL-10敲除小鼠的静脉移植物以及治疗后的导管外源性IL-10（药理学和AAV vIL-10）。根据申请人在研究培训期间获得的新知识和技能，这个最初的独立提案的设计是将基本的细胞因子生物学转移到血管生物学，通过新的机械见解，将这些发现转化为策略，以提高静脉筏的耐久性。