Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling

内外不平衡动静脉内瘘重塑机制

• 批准号: 10292935
• 负责人: YAN-TING E. SHIU
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292935
• 关键词: Arteriovenous fistula; Automobile Driving; Blood Vessels; Blood flow; Cardiovascular Diseases; Caring; Cell Wall; Chronic; Chronic Kidney Failure; Clinical; Coculture Techniques; Development; Diagnostic; Dialysis procedure; Disease; End stage renal failure; Endothelial Cells; Endothelium; Enrollment; Etiology; Failure; Functional disorder; Goals; Health Care Costs; Healthcare Systems; Hemodialysis; Homeostasis; Human; Hyperplasia; Impairment; Inflammasome; Kidney; Knock-out; Lead; Link; Mediating; MicroRNAs; Modality; Modeling; Molecular; Morbidity - disease rate; Mus; NOS3 gene; Nanotechnology; Outcome; Pathogenesis; Pathologic; Pathway interactions; Patients; Play; Process; Production; Rattus; Renal function; Research; Role; Serum; Smooth Muscle Myocytes; Source; Testing; Therapeutic; Tissues; Transgenic Mice; Up-Regulation; Uremia; Vasodilation; Venous; Veterans; Wild Type Mouse; base; cardiovascular health; cost effective; genetic approach; hemodynamics; human model; improved; inhibitor; innovation; mortality; nanomedicine; nanoparticle; novel; overexpression; success; therapeutic target; vascular inflammation

The inability of arteriovenous fistulas (AVFs) to mature sufficiently for adequate dialysis is a major clinical problem confronting chronic hemodialysis. Up to 60% of newly created AVFs fail to mature, and currently there is no effective strategy to enhance AVF maturation. AVF maturation failure results from an imbalance between inward remodeling due to venous neointimal hyperplasia and outward remodeling due to sustained venous dilation. Although inward remodeling has been intensively studied, the contribution of outward remodeling to AVF maturation remains largely unexplored. Effective strategies for enhancing AVF maturation should promote sustained venous dilation while inhibiting hyperplasia. Therefore, it is critically important to identify therapeutic targets that modulate both processes. MicroRNAs (miRs) are crucial modulators in cardiovascular health and diseases, and miR-targeting strategies have been shown to be promising diagnostics and therapeutics in these diseases. However, the role of miRs in modulating AVF maturation has not been explored. We have generated novel results suggesting that microRNA-92a (miR-92a), a key regulator in vascular homeostasis, is a major contributor to pathological AVF remodeling. Accordingly, this project aims to determine the causal role of increased miR-92a in driving AVF maturation failure, and to investigate the efficacy of miR-92a inhibition by targeted nanomedicine in enhancing AVF maturation. Our over-arching hypothesis is that upregulation of endothelial miR-92a by chronic kidney disease (CKD) and AVF-associated aberrant blood flow causes maturation failure through two mechanisms, i.e., impairing vasodilation (outward remodeling) and promoting neointimal hyperplasia (inward remodeling). To test this hypothesis, we propose three Specific Aims. These aims use genetic approaches and targeted nanotechnology to systematically determine the causal role of miR-92a in AVF maturation failure, advancing from miR-92a in the whole body to the inflamed endothelium. Specific Aim 1 is to determine the causal role of miR-92a in pathological AVF development in mice with CKD. We will create AVF in whole-body miR-92a knockout and wild-type mice with CKD, and determine whether systemic knockout results in greater outward and less inward AVF remodeling. Specific Aim 2 is to investigate whether AVF development is impaired in transgenic mice overexpressing endothelial miR-92a. We will create AVF in mice overexpression endothelial miR-92a and in control mice, and determine whether transgenic mice have impaired outward and exaggerated inward AVF remodeling. Specific Aim 3 is to investigate the therapeutic potency of miR-92a inhibition by inflamed-endothelium targeting nanomedicine in enhancing AVF development in rats with CKD. We will determine whether nanoparticles that target inflamed ECs and contain miR-92a inhibitors can promote outward and inhibit inward AVF remodeling in rats with CKD. These studies are expected to identify the novel role of the important miR-92a pathway in the pathogenesis of AVF maturation failure. Our results will provide the first cause-and-effect evidence linking miR- 92a to AVF maturation failure, and provide an important rationale for developing innovative therapeutics that aims to target miR-92a to enhance AVF maturation, a huge unmet clinical need.

动静脉瘘(AVF)不能充分成熟以进行充分的透析是一个主要原因 慢性血液透析面临的临床问题。高达60%的新创建的AVF未能成熟，以及 目前还没有有效的策略来促进动静脉曲张的成熟。AVF成熟失败的原因是 静脉新生内膜增生性内向重构与外向重构的失衡 静脉持续扩张。尽管人们对内向重塑进行了深入的研究，但 向外重构到房室瘘成熟在很大程度上仍未被探索。提高AVF的有效策略 成熟应该促进持续的静脉扩张，同时抑制增殖。因此，它是至关重要的 重要的是确定调节这两个过程的治疗靶点。 MicroRNAs(MiRs)在心血管健康和疾病中是至关重要的调节器，并且miR靶向 这些策略在这些疾病的诊断和治疗中显示出了良好的前景。然而，这个角色 MIR在调节AVF成熟中的作用还没有被探索。我们产生了新的结果，表明 MicroRNA-92a(miR-92a)是血管内稳态的关键调节因子，是导致病理改变的主要因素。 AVF重塑。因此，该项目旨在确定增加的miR-92a在驾驶中的因果作用 AvF成熟失败，并研究靶向纳米药物对miR-92a的抑制作用 促进AVF成熟。 我们最重要的假设是慢性肾脏疾病导致内皮细胞miR-92a上调 (CKD)和AVF相关的异常血流通过两种机制导致成熟失败，即， 损害血管扩张(外向重塑)，促进新生内膜增生(内向重塑)。为了测试 在这一假设下，我们提出了三个具体目标。这些目标使用遗传方法和有针对性的 纳米技术系统地确定miR-92a在AVF成熟失败、进展中的原因作用 从全身的miR-92a到炎症的内皮细胞。具体目标1是确定 MIR-92a在慢性肾脏病小鼠病理性动静脉瘘发生中的作用我们将在全身miR-92a中创建AVF CKD基因敲除和野生型小鼠，并确定系统性基因敲除是否会导致更大的外向 以及较少的向内AVF重塑。具体目的2是调查AVF的发育是否在 转基因小鼠过表达内皮细胞miR-92a。我们将在小鼠过表达的内皮细胞中创建AVF MIR-92a和对照组小鼠，并确定转基因小鼠是否向外受损和夸大 向内AVF重塑。具体目标3是研究miR-92a抑制的治疗效力，通过 炎症内皮靶向纳米药物促进慢性肾脏病大鼠动静脉瘘的发生。我们会 确定靶向炎症内皮细胞并含有miR-92a抑制剂的纳米颗粒是否可以促进向外 抑制慢性肾功能不全大鼠内向AVF重构。 这些研究有望确定重要的miR-92a途径在 房室瘘成熟失败的发病机制。我们的结果将提供第一个将miR- 92a至AVF成熟失败，并为开发创新疗法提供了重要的理论基础 旨在以miR-92a为靶点促进AVF成熟，这是一个巨大的未得到满足的临床需求。