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

血液透析 AVF 狭窄形成中的调控基因-趋化因子网络

• 批准号: 10253421
• 负责人: RAJIV KUMAR
• 金额: $ 10.34万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-25 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253421
• 关键词: Adoption; Affect; American; Angioplasty; Arteriovenous fistula; Attenuated; Award; Balloon Angioplasty; Blood Vessels; Blood flow; CCL2 gene; Cell Proliferation; Cellular Infiltration; Chronic Kidney Failure; Clinical; Clinical Trials; Data; Development; Devices; Diagnosis; Disease model; Dose; ERG gene; End stage renal failure; Endothelium; Failure; Family suidae; Fibroblasts; Fibrosis; Functional disorder; Funding; Future; Gene Expression; Goals; Health; Health Care Costs; Hemodialysis; Histologic; Human; Hyperplasia; Image; Incidence; Infiltration; Injury; Kidney; Knowledge; Maintenance; Measures; Mechanics; Modeling; Modulus; Morbidity - disease rate; Mus; Paclitaxel; Pathogenesis; Patients; Peripheral arterial disease; Pharmacology; Phase I Clinical Trials; Physiologic pulse; Preparation; Prevention; Process; Recurrence; Regulator Genes; Renal Replacement Therapy; Research; Rodent; Role; Smooth Muscle Myocytes; Stenosis; Stents; Stretching; Symptoms; Technology; Testing; Therapeutic; Treatment Cost; Ultrasonography; Vascular Patency; Veins; Venous; base; chemokine; clinical practice; cost; effective therapy; efficacy study; efficacy testing; evidence base; innovation; knock-down; macrophage; monocyte; mortality; mouse Cre recombinase; nanoparticle; novel therapeutics; prevent; response

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.

摘要/摘要： 动静脉瘘（AVF）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)，导致最终血液透析 (HD) 的 AVF 血流量减少 阶段肾病（ESRD）患者。此次更新的长期目标是： 1. 定义 VS 的机制 PTA 后 AVF 中出现 VNH； 2. 开发新的药物疗法以减轻 AVF 中的 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，美国有 726,331 名患者（全球约 200 万）被诊断患有 ESRD，发病率每年增加 3%。 大约 87% 的 ESRD 患者接受 HD 肾脏替代治疗。最佳的长期 HD 需要 通过 AVF 或移植物建立血管通路。 AVF一年通畅率仅62%，频繁重复血管成形术 维护费用>$3B/年。血管成形术后 AVF VS/VNH 的机制尚不清楚。疗法 预防 VS/VNH（PTA 后 AVF 失败的主要原因）将大大降低发病率和医疗费用 对 ESRD 患者有益。 在先前的奖项中（为期 3 年且资金减少），我们研究了 1,25(OH)2D3- 外膜递送的功效 将涂层纳米颗粒 (1,25 NP) 注入 AVF 流出静脉，以减少患有慢性肾病的小鼠和猪的 VNH （CKD）。我们发现用 1,25 NP 治疗 AVF 可以减少 AVF 的 VNH 和 VS、巨噬细胞的数量、 平滑肌细胞 (SMC) 和成纤维细胞、立即早期反应基因 (Iex-1/Ier3) 表达和细胞 增殖，导致流出静脉纤维化减少。该提案检查了 PTA 后 AVF 失败的病理生理学 对此尚无有效的治疗方法。最近使用紫杉醇涂层技术的试验产生了不同的结果—— 由于接受这些治疗的患者全因死亡率增加，临床实践的采用已经减少 用于治疗外周动脉疾病症状的设备。 需要基于机制观察的新疗法来预防 PTA 后的 VS/VNH。作为回应，我们 开发了用 PTA 治疗的狭窄 AVF 的小鼠和猪 CKD 模型，并获得了建立数据 Ier3/Iex-1 的核心作用和 单核细胞趋化蛋白-1 (Mcp-1/Ccl2) 驱动细胞浸润 AVF VS 的发病机制。 PTA 后将 1,25 NP 外膜递送至狭窄静脉可减少 VS 和 VNH 我们模型中的 AVF。此应用检查 PTA 后 VS/VNH 的机制，测试 1,25NP 功效 在小鼠和猪模型中进行未来的临床试验。 中心假设：用外膜 1,25NP 治疗血管成形术后狭窄的流出静脉将减少 SMC Ier3 和随后的 Mcp-1/Ccl2 表达以及单核细胞和巨噬细胞的血管壁浸润导致 减少 VS 和 VNH。为了检验这个假设，我们提出两个目标： 目标 1：评估小鼠 AVF PTA 后 SMC Ier3 缺失和 Mcp-1/Ccl2 敲低对 VS/VNH 的作用。 目标 2：确定 1,25 NP 在啮齿动物和 PTA 后减少 AVF VS/VNH 的作用机制和效果 CKD 猪模型。