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)，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发挥功能的 AVF 子集最终不再发挥作用。 AVF失败主要反映3个过程：新生内膜增生、血管舒张受损和异常动脉重塑以及血栓形成。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，我们利用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，以及失败的人类 AVF 的关键特征，包括新内膜增生、血栓形成和血管病变基因的诱导。在这些模型中，我们证明了促炎转录因子（NF-κB 和 AP-1）的激活，以及适应不良的血管病变基因（MCP-1）和适应性血管保护基因（eNOS 和 HO-1）的上调。我们提出的目标以结束周期中的发现为基础，包括以下内容。目的 I. 假设：NOS 系统决定 AVF 的适应和损伤。考试。使用大鼠 AVF 模型，该目标将检查特定 NOS 亚型的作用，以及 NOS 辅因子、BH4 和超氧阴离子清除是否决定 AVF 的表型。这些研究将通过使用突变小鼠来检查特定 NOS 亚型、GTP 环化水解酶（BH4 合成酶）和内源性 NOS 抑制剂、不对称二甲基精氨酸 (ADMA) 的作用的策略来补充。目标二。假设：HO 及其产品可防止 AVF 失败。检查：此目的将确定 HO-1-/- 小鼠的过早 AVF 衰竭是否涉及动脉血流和血管反应性受损、NF-κB 和 AP-1 激活增加和/或组织因子依赖性血栓形成。该目标将确定 HO 产品（一氧化碳和胆汁色素）对 HO-1+/+ 小鼠 AVF 病理学的影响，以及这些产品是否可以减轻 HO-1-/- 小鼠 AVF 的过早衰竭；还将评估 H2O2 诱导在保护 AVF 方面的效果。最后，将确定 HO-2（组成型 HO 同工酶）对 AVF 的潜在保护作用。目标三。假设：MCP-1 上游和下游的介体导致 AVF 失败。检查：此目的将检查 MCP-1 mRNA 上游中间体（即 NF-κB 和 AP-1）以及 MCP-1 mRNA 下游中间体（特别是 MCP-1 蛋白和 MCP-1 受体）的作用（ CCR2）。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 抑制剂来检查 CCL5 在 AVF 失败中的作用。因此，本申请研究了血管生物学中的 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不久预期的小分子治疗途径。