Mechanism of Dialysis Arteriovenous Fistula Dysfunction

透析动静脉内瘘功能障碍的机制

• 批准号: 8334635
• 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
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-03 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334635
• 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

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-?B 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-?B 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-?B 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（由申请人提供）：血液透析血管通路功能障碍是慢性血液透析患者发病率和死亡率的最重要因素。即使是最有利的血管通路，动静脉瘘（AVF），其结果也是令人沮丧的，高达60%的AVF从未发挥作用，并且越来越多的曾经有功能的AVF最终停止发挥作用。AVF衰竭主要反映3个过程：新生内膜增生、血管松弛受损和动脉重构异常、血栓形成。本申请旨在继续检查AVF功能障碍的基础，并探索相关的治疗策略。在完整的周期中，我们使用了外周手术创建的啮齿动物AVF模型，证明这些模型概括了功能性人类AVF的基本特征，包括血流量增加，以及衰竭的人类AVF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，我们证实了促炎转录因子(NF-？B和AP-1)，以及适应性血管病变基因（MCP-1）和适应性血管保护基因（eNOS和HO-1）的上调。我们在结束的周期的调查结果的基础上提出的目标包括以下内容。假设：NOS系统决定了AVF的适应和损伤。检查。利用大鼠AVF模型，本目的将研究特异性NOS亚型的作用，以及NOS辅助因子、BH4和超氧阴离子清除是否决定AVF的表型。这些研究将通过采用突变小鼠的策略来补充研究特异性NOS异构体、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。目的二世。假设：HO及其产物可防止AVF失效。检查：目的是确定HO-1-/-小鼠过早AVF衰竭是否涉及动脉血流和血管反应性受损、NF-？B和AP-1激活，和/或组织因子依赖性血栓形成。本研究旨在确定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，以及这些产物是否可以减轻HO-1-/-小鼠AVF的过早衰竭；我们还将评估HO诱导对AVF的保护作用。最后，确定HO同工酶HO-2在AVF中的潜在保护作用。第三目标。假设：MCP-1的上游和下游介质与AVF衰竭有关。检查：本目的将检查MCP-1 mRNA上游中间体的作用，即NF-？B和AP-1，以及MCP-1 mRNA的下游中间体，特别是MCP-1蛋白和MCP-1受体（CCR2）。由于我们在AVF中的研究结果表明MCP-1可能通过RANTES （CCL5）发挥其不良作用，因此我们将使用CCL5-/-小鼠和CCL5抑制剂来研究CCL5在AVF衰竭中的作用。因此，该应用程序研究了血管生物学中3个基本重要系统如何决定AVF的成功或失败，并可能揭示制药行业预期不久的小分子治疗途径。