Regulatory gene-chemokine networks in the formation of hemodialysis AVF stenosis

摘要/摘要： 动静脉瘘术后常出现静脉狭窄(VS)和新生内膜增生(VNH)。 经皮腔内血管成形术(PTA)导致终末期血液透析(HD)的AVF血流量减少 肾脏疾病(ESRD)期患者。此次更新的长期目标是：1.定义与 2.开发新的药物治疗以减轻动静脉瘘的VS/VNH 在啮齿动物/猪模型中进行PTA后，用于未来的临床试验。 2016年，726,331名美国患者(全球约200万人)被诊断为ESRD，发病率每年上升3%。 大约87%的终末期肾病患者接受HD的肾脏替代治疗。最佳的长期高清需要 通过动静脉瘘或移植物进行血管通路。动静脉瘘一年通畅率仅为62%，经常重复血管成形术 &gt；的维护费为每年30亿美元。血管成形术后AVF VS/VNH的机制尚不清楚。治疗方法 预防VS/VNH，这是PTA后AVF失败的主要原因，将减少发病率和医疗成本， 对终末期肾病患者的益处。 在之前的奖项中(为期3年，资金减少)，我们研究了外膜递送1，25(OH)2D3-的疗效。 AVF流出静脉内包被纳米粒(1，25-NP)减少慢性肾脏病小鼠和猪的VNH (CKD)。我们发现用1，25 NP治疗动静脉瘘可以降低动静脉瘘的VNH和VS，减少巨噬细胞的数量， 平滑肌细胞和成纤维细胞、即刻早期反应基因IEX-1/Ier3的表达与细胞 增殖，导致流出静脉纤维化较少。这项建议检查PTA术后AVF衰竭的病理生理学。 目前还没有有效的治疗方法。最近使用紫杉醇包衣技术的试验结果喜忧参半- 临床实践的采用已经减少，因为使用这些药物治疗的患者的全因死亡率增加。 用于外周动脉疾病症状的设备。 需要基于机械观察的新疗法来预防PTA术后的VS/VNH。作为回应，我们 PTA治疗狭窄动静脉瘘的小鼠和猪CKD模型的建立及数据建立 Ier3/IEX-1和 单核细胞趋化蛋白-1(MCP-1/CCL2)诱导的细胞浸润 AVF与VS的发病机制。经皮腔内成形术后血管外膜递送1，25-NP可减少VS和VNH Avf在我们的模型中。该应用程序检测PTA后VS/VNH的机制，测试1，25NP的疗效 在小鼠和猪的模型中用于未来的临床试验。 中心假设：外膜1，25NP治疗血管成形术后狭窄流出静脉将降低SMC Ier3及随后的MCP-1/CCL2表达和单核/巨噬细胞对血管壁的侵袭导致 较少的VS和VNH。为了验证这一假设，我们提出了两个目标： 目的1：探讨SMC Ier3缺失和MCP-1/CCL2基因敲除在小鼠动静脉瘘PTA后VS/VNH中的作用(S)。 目的：探讨1，25-NP降低大鼠PTA后AVF VS/VNH的作用机制及作用机制。 慢性肾脏病猪模型。

SUMMARY/ABSTRACT: Venous stenosis (VS) and neointimal hyperplasia (VNH) often occur in arteriovenous fistulas (AVFs) after percutaneous transluminal angioplasty (PTA), leading to reduced AVF blood flow for hemodialysis (HD) in end- stage renal disease (ESRD) patients. This renewal's long-term goals are to: 1. Define mechanisms by which VS and VNH occur in AVFs after PTA; and 2. Develop new pharmacologic therapies to attenuate VS/VNH in AVFs after PTA in rodent/porcine models for a future clinical trial. In 2016, 726,331 US patients (~2M globally) were diagnosed with ESRD, with an annual 3% rising incidence. Roughly 87% of ESRD patients undergo renal replacement therapy with HD. Optimal long-term HD necessitates vascular access via AVFs or grafts. One year AVF patency rate is only 62%, with frequently repeated angioplasty maintenance at >$3B/yr. The mechanisms underpinning AVF VS/VNH after angioplasty are unknown. Therapies preventing VS/VNH, the major cause of AVF failure after PTA, will reduce morbidity and healthcare costs, of huge benefit to patients with ESRD. In the prior award (with 3 years and reduced funding), we studied the efficacy of adventitial delivery of 1,25(OH)2D3- coated nanoparticles (1,25 NP) to the AVF outflow vein to reduce VNH in mice and pigs with chronic kidney disease (CKD). We showed treatment of AVFs with 1,25 NP reduces VNH and VS of AVFs, the number of macrophages, smooth muscle cells (SMC) and fibroblasts, immediate early response gene (Iex-1/Ier3) expression and cellular proliferation, leads to less outflow vein fibrosis. This proposal examines AVF failure pathophysiology following PTA for which no effective therapies exist. Recent trials using paclitaxel coated technologies yielded mixed results— clinical practice adoption has been diminished due to increased all-cause mortality in patients treated with these devices for peripheral arterial disease symptoms. New therapies based on mechanistic observations are needed to prevent VS/VNH after PTA. In response, we developed murine and porcine models of CKD with stenotic AVFs treated with PTA and obtained data establishing the central role of Ier3/Iex-1 and monocyte chemoattractant protein-1 (Mcp-1/Ccl2) driven cellular infiltration in the pathogenesis of AVF VS. Adventitial delivery of 1,25 NP to the stenotic vein after PTA reduced VS and VNH in AVFs in our models. This application examines the mechanism of VS/VNH following PTA, testing 1,25NP efficacy in both murine and porcine models for a future clinical trial. Central Hypothesis: Treatment of stenotic outflow veins after angioplasty with adventitial 1,25NP will reduce SMC Ier3 and subsequent Mcp-1/Ccl2 expression and vessel wall infiltration by monocytes and macrophages resulting in less VS and VNH. To test this hypothesis, we propose two aims: Aim 1: Assess the role(s) of SMC Ier3 deletion and Mcp-1/Ccl2 knockdown on VS/VNH after PTA of murine AVFs. Aim 2: Determine the mechanism of action and effect of 1,25 NP on reducing AVF VS/VNH after PTA in rodent and porcine models of CKD.