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）：血液透析血管访问功能障碍是导致患者发病率和死亡率的最重要的慢性血液透析。即使是最有利的血管进入的结果，动脉瘘（AVF）也令人沮丧，高达60％的AVF从未运行，并且增加了一次功能性AVF的子集最终停止这样做。 AVF故障在很大程度上反映了3个过程：新内膜增生，血管瘤障碍和异常动脉重塑以及血栓形成。该申请旨在继续检查AVF功能障碍的基础和相关治疗策略的探索。在完整的周期中，我们利用了外围，手术创建的啮齿动物AVF模型，表明这些模型概括了功能性人AVF的基本特征，包括增加的血液流量以及失败的人AVF的关键特征，包括Neinimail Spryplasia，Thrombasisia，Thromombosis，Thrombosis，thrombosis和诱导血管病毒基因。在这些模型中，我们证明了促炎转录因子（NF-？b和ap-1）的激活，以及适应性疾病，血管疗法基因（MCP-1）和适应性，血管保护基因（ENOS和HOO-1）的上调。我们提出的目标是在结束周期中提出的发现和建立，包括以下内容。 AIM I.假设：NOS系统决定了AVF的适应和伤害。考试。使用大鼠AVF模型，此目标将检查特定的NOS同工型的作用，以及NOS辅因子，BH4和超氧化物阴离子是否确定AVF的表型。这些研究将通过采用突变小鼠来检查特定NOS同工型，GTP环氧化氢酶（BH4合成酶）和内源性NOS抑制剂，非对称二甲基氨基氨酸（ADMA）的作用来补充。目标II。假设：HO及其产品可以防止AVF失败。检查：此目标将确定HO-1 - / - 小鼠中的AVF衰竭是否涉及动脉血流受损和血管反应性受损，NF-？B和AP-1激活增加以及/或组织因子依赖性血栓形成。该目标将确定HO产品（一氧化碳和胆汁颜料）对HO-1+/+小鼠AVF病理生物学的影响，以及这些产品是否可以减轻HO-1 - / - 小鼠中AVF的过早失败； HO诱导保护AVF的影响也将得到评估。最后，将确定HO-2的AVF中的潜在保护作用，即组成型Hosozyme。目标三。假设：MCP-1上游和下游的介体导致AVF失败。检查：此目标将检查MCP-1 mRNA上游的中间体的作用，即NF-？B和AP-1，以及MCP-1 mRNA下游的中间体，特别是MCP-1蛋白和MCP-1受体（CCR2）。正如我们在AVF中的发现表明，MCP-1可以通过RANTES（CCL5）发挥其不良反应，CCL5在AVF失败中的作用将使用CCL5 - / - 小鼠和CCL5抑制剂进行检查。因此，该应用研究了血管生物学中的3个重要系统如何确定AVF成功或失败，并可能披露了预期从制药行业预期的小分子的治疗途径。