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Mechanism of Dialysis Arteriovenous Fistula Dysfunction

透析动静脉内瘘功能障碍的机制

基本信息

批准号：
8919337
负责人：
KARL A. NATH
金额：
$ 34.3万
依托单位：
MAYO CLINIC ROCHESTER
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：
2005-02-03 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8919337
关键词：
Adverse effects Anabolism Anastomosis - action Applications Grants Arteries Arteriovenous fistula Artificial Kidney Attenuated Bile Pigments Biology Blood Blood Vessels Blood flow CCL2 gene Carbon Monoxide Chemicals Chronic Chronic Kidney Failure Coagulation Process Complement Development Dialysis patients Dialysis procedure Drug Industry Enzymes Exhibits Failure Fistula Functional disorder Funding GTP Cyclohydrolase Gene Proteins Genes Hemodialysis Human Hyperplasia Injury Isoenzymes Lead Mediator of activation protein Messenger RNA Modeling Molecular Morbidity - disease rate Mus Mutant Strains Mice N,N-dimethylarginine Outcome Patients Peripheral Phenotype Process Protein Isoforms Proteins Publishing RANTES Rattus Research Resistance Rest Rodent Role Site Superoxides Surgical Anastomosis System Therapeutic Thromboplastin Thrombosis Time Transcription Factor AP-1 Up-Regulation Upper Extremity Vasodilation Veins Venous Work arterial remodeling attenuation base cofactor heme oxygenase-1 inhibitor/antagonist monocyte chemoattractant protein 1 receptor mortality premature prevent protective effect small molecule success tetrahydrobiopterin transcription factor

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of hemodialysis vascular access is the single most important contributor to the morbidity and mortality of patients on chronic hemodialysis. The outcome for even the most favored vascular access, the arteriovenous fistula (AVF), is dismal with up to 60% of AVFs never functioning, and increasing subsets of once functional AVFs eventually ceasing to do so. AVF failure largely reflects 3 processes: neointimal hyperplasia, impaired vasorelaxation and aberrant arterial remodeling, and thrombosis. This application seeks to continue the examination of the basis for AVF dysfunction and the exploration of relevant therapeutic strategies. In the completed cycle, we utilized peripheral, surgically-created rodent AVF models, demonstrating that these models recapitulate the essential features of functional human AVFs, including increased blood flow, and the critical features of failing human AVFs, including neointimal hyperplasia, thrombosis, and induction of vasculopathic genes. In these models, we demonstrate activation of proinflammatory transcription factors (NF-κB and AP-1), and the upregulation of maladaptive, vasculopathic genes (MCP-1) and adaptive, vasoprotective genes (eNOS and HO-1). Our proposed aims, resting and building on findings made in the concluded cycle, include the following. AIM I. Hypothesis: The NOS system determines adaptation and injury in the AVF. Examination. Using the rat AVF model, this aim will examine the role of specific NOS isoforms, and whether the NOS cofactor, BH4, and superoxide anion scavenging determine the phenotype of the AVF. These studies will be complemented by strategies employing mutant mice to examine the roles of specific NOS isoforms, GTP cyclohydrolase (the BH4-synthesizing enzyme), and endogenous NOS inhibitor, asymmetric dimethylarginine (ADMA). AIM II. Hypothesis: HO and its products protect against AVF failure. Examination: This aim will determine whether the premature AVF failure in HO-1-/- mice involves impaired arterial blood flow and vascular reactivity, increased NF-κB and AP-1 activation, and/or tissue factor-dependent thrombosis. This aim will determine the effects of HO products (carbon monoxide and bile pigments) on AVF pathobiology in HO-1+/+ mice, and whether these products can attenuate the premature failure of AVFs in HO-1-/- mice; the effect of HO induction in protecting the AVF will also be assessed. Finally, the potential protective effects in the AVF of HO-2, the constitutive HO isozyme, will be determined. AIM III. Hypothesis: Mediators upstream and downstream of MCP-1 contribute to AVF failure. Examination: This aim will examine the role of intermediates upstream of MCP-1 mRNA, namely, NF-κB and AP-1, and intermediates downstream of MCP-1 mRNA, specifically, MCP-1 protein and the MCP-1 receptor (CCR2). As our findings in the AVF suggest that MCP-1 may exert its adverse effects via RANTES (CCL5), the role of CCL5 in AVF failure will be examined using CCL5-/- mice and a CCL5 inhibitor. This application thus examines how 3 fundamentally important systems in vascular biology determine AVF success or failure, and may disclose therapeutic avenues for small molecules expected shortly from the pharmaceutical industry.

描述(申请人提供)：血液透析血管通路障碍是导致慢性血液透析患者发病率和死亡率的最重要因素。即使是最受欢迎的血管通路，动静脉瘘(AVF)的结果也是令人沮丧的，高达60%的AVF从未发挥作用，而且越来越多的曾经具有功能的AVF亚群最终停止了这种作用。AVF的失败主要反映了3个过程：新生内膜增生、血管松弛受损、异常的动脉重构和血栓形成。这项申请旨在继续检查AVF功能障碍的基础并探索相关的治疗策略。在完成的周期中，我们利用外周的、通过手术创建的啮齿动物动静脉瘘模型，展示了这些模型概括了功能性人类动静脉动静脉瘘的基本特征，包括血流量增加，以及失败的人类动静脉动静脉瘘的关键特征，包括新生内膜增生、血栓形成和血管病变基因的诱导。在这些模型中，我们证明了促炎症转录因子的激活。 (核因子-κB和AP-1)，以及不适应、血管病变基因(mCP-1)和适应性血管保护基因(eNOS和HO-1)的上调。我们建议的目标包括以下内容，这些目标立足于并建立在已结束的周期中取得的调查结果之上。目的I.假设：一氧化氮合酶系统决定动静脉动静脉瘘的适应和损伤。考试。利用大鼠动静脉瘘模型，这一目的将检验特定的一氧化氮合酶亚型的作用，以及一氧化氮合酶辅助因子、BH4和超氧阴离子清除是否决定动静脉动静脉瘘的表型。这些研究将得到利用突变小鼠研究特定NOS亚型、GTP环水解酶(BH4合成酶)和内源性NOS抑制剂不对称二甲基精氨酸(ADMA)的作用的策略的补充。目的II.假设：HO及其产品对AVF失效有保护作用。检查：这一目标将确定HO-1-/-小鼠过早的动静脉动静脉瘘是否涉及动脉血流和血管反应性受损，核因子-κB和AP-1活性增加，和/或组织因子依赖的血栓形成。这一目的将确定HO产物(一氧化碳和胆汁色素)对HO-1+/+小鼠AVF病理生物学的影响，以及这些产品是否能够减轻HO-1-/-小鼠AVF的过早衰竭；还将评估HO诱导对AVF的保护作用。最后，将确定构成HO同工酶HO-2在AVF中的潜在保护作用。目的III.假设：单核细胞趋化蛋白-1的上下游介质参与了动静脉动静脉瘘的失败。目的：研究单核细胞趋化蛋白1mRNA上游的中间体，即核因子κB和AP-1，以及单核细胞趋化蛋白1mRNA下游的中间体，特别是单核细胞趋化蛋白1蛋白和单核细胞趋化蛋白1受体。由于我们在AVF中的发现表明，MCP-1可能通过RANTES(CCL5)发挥其不利影响，因此将使用CCL5-/-小鼠和CCL5抑制剂来研究CCL5在AVF失败中的作用。因此，这项应用研究了血管生物学中三个基本的重要系统如何决定AVF的成功或失败，并可能揭示制药行业不久将推出的小分子治疗途径。