Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling

动静脉瘘（AVF）不能充分成熟以进行充分透析是一个主要的问题， 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， 目前还没有有效的策略来提高AVF成熟。AVF成熟失败的原因是 静脉新生内膜增生引起的向内重塑和 持续的静脉扩张虽然向内重塑已经被深入研究，但 AVF成熟的向外重塑在很大程度上尚未探索。增强AVF的有效策略 成熟应促进持续的静脉扩张，同时抑制增生。因此， 重要的是确定调节这两个过程的治疗靶点。 microRNAs（miRs）是心血管健康和疾病的重要调节因子， 这些策略已被证明是这些疾病中有前途的诊断和治疗方法。然而，作用 miR在调节AVF成熟中的作用尚未研究。我们得出了新的结果， 微RNA-92 a（miR-92 a）是血管稳态的关键调节因子，是病理性 AVF重塑。因此，本项目旨在确定增加的miR-92 a在驱动细胞凋亡中的因果作用。 AVF成熟失败，并研究靶向纳米药物抑制miR-92 a在AVF成熟失败中的功效。 促进AVF成熟。 我们的过度假设是，慢性肾脏疾病引起的内皮细胞miR-92 a的上调 (CKD)AVF相关的异常血流通过两种机制引起成熟失败，即， 损害血管舒张（向外重塑）和促进新生内膜增生（向内重塑）。测试 针对这一假设，我们提出了三个具体目标。这些目标使用遗传方法， 纳米技术系统地确定miR-92 a在AVF成熟失败中的因果作用， 从全身的miR-92 a到发炎的内皮。具体目标1是确定以下因素的因果作用： miR-92 a在CKD小鼠病理性AVF发展中的作用我们将在全身miR-92 a中创建AVF 敲除和野生型CKD小鼠，并确定系统性敲除是否会导致更大的外向 和较少的内向AVF重塑。具体目标2是研究AVF发育是否受损， 过表达内皮miR-92 a的转基因小鼠。我们将在小鼠中建立AVF，过度表达内皮细胞 miR-92 a和对照小鼠中，并确定转基因小鼠是否具有受损的外向和夸大的 内向AVF重构。具体目的3是研究通过以下方法抑制miR-92 a的治疗效力： 炎症内皮靶向纳米药物促进CKD大鼠AVF发展。我们将 确定靶向发炎EC并含有miR-92 a抑制剂的纳米颗粒是否可以促进细胞外基质的形成， 抑制CKD大鼠AVF内向性重构。 这些研究有望确定重要的miR-92 a通路在肿瘤发生中的新作用。 AVF成熟失败的发病机制。我们的研究结果将提供第一个因果证据， 92 a至AVF成熟失败，并为开发创新疗法提供了重要依据， 旨在靶向miR-92 a以增强AVF成熟，这是一个巨大的未满足的临床需求。

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.