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：
7756800
负责人：
C KEITH OZAKI
金额：
$ 27.54万
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：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756800
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 Facility Construction Funding Category Failure Future Hand Homologous Gene Hour Hyperplasia Infiltration Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-1 Interleukin-10 Intervention Knockout Mice Knowledge Laboratories Leukocytes Link Lower Extremity Mediating Mediator of activation protein 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 Tumor Necrosis Factor-alpha Veins Viral Work base body system cell motility cytokine cytokine therapy design exhaust graft failure human MPP1 protein human TNF 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

DESCRIPTION (provided by applicant): 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 proinflammatory cytokine TNF-alpha 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-alpha 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-alpha 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-alpha or the p55 or p75 receptor. Under differential flow environments, TNF-alpha 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-alpha 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-alpha 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 through new mechanistic insights, translate these findings into strateqies to improve vein (draft durability).

描述（由申请人提供）：手术静脉旁路移植物主要是由于新内膜增生的发展而失败，尤其是在导管内低流量的情况下。炎症是该过程的病理特征。虽然细胞因子与静脉移植衰竭有关，但其表达的启动因子和信号传导机制（以及这些炎症介质在静脉壁适应中的生物学意义）仍然在很大程度上未知。我们小组的先前研究直接暗示了促炎性细胞因子TNF-α和抗炎细胞因子IL-10的产生，以调节动脉壁适应壁剪的变化。在最近的工作中，我们证明了早期动脉化静脉移植物中的特定时间和依赖性细胞因子特征。在低流量移植物中，在24小时内诱导了TNF-α表达，随后会产生强大的内膜增生，而高流量则促进了IL-10 mRNA表达的延迟诱导，这似乎可以防止闭塞性适应。该提案通过测试两个链接的机械假设来向前发展：1）静脉移植通过低壁剪切诱导的促炎细胞因子驱动的机制（可溶性TNF-Alpha信号传导）（通过p55受体传导）发展了新的增生增生。细胞增殖增加）。信号通路将通过研究缺乏可溶性TNF-Alpha或p55或p75受体的小鼠中的静脉移植物来阐述。在差分流动环境下，将通过可溶性受体抑制TNF-α信号传导，腺体相关病毒（AAV）降低的TNF受体同源物，特定的p55或p75 TNF受体抗体或TNF-Alpha转化enzyme抑制。 2）IL-10产生通过减少炎症白细胞浸润，肌纤维细胞增殖和TNF-α产生下调，可保护静脉移植物免受过度闭塞壁的适应。将检查来自IL-10基因敲除小鼠的静脉移植物，以及用外源IL-10（药理学和AAV VIL-10）处理后的导管。基于在申请人的研究培训期间获得的新知识和技能，该最初独立建议的基本设计是将基本的细胞因子生物学转移到血管生物学上，并通过新的机械洞察力将这些发现转化为改善静脉的策略（耐用性草案）。