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.

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