Monocyte chemoattractant Proteins and Vascular Injury

单核细胞趋化蛋白与血管损伤

• 批准号: 10732564
• 负责人: Sanjay Misra
• 金额: $ 71.02万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732564
• 关键词: Affect; American; Angioplasty; Animals; Arteries; Arteriovenous fistula; Balloon Angioplasty; Binding; Blood Vessels; Blood flow; CCL2 gene; CCL7 gene; CCL8 gene; Cd68; Cell Adhesion Molecules; Cells; Chemotaxis; Clinical; Data; Development; Devices; Diagnosis; Disease Outcome; Doppler Ultrasound; Drug Kinetics; Electron Microscope; Encapsulated; End stage renal failure; Endothelial Cells; Endothelium; Family suidae; Fibrosis; Functional disorder; Gene Expression; Genes; Glycolates; Goals; Hemodialysis; Histologic; Hydrogels; Hyperplasia; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Intercellular adhesion molecule 1; Interleukin-8; Kidney Diseases; Legal patent; Letters; Leukocytes; Liposomes; Liquid Chromatography; Macrophage; Messenger RNA; Modulus; Molecular; Molecular Chaperones; Monocyte Chemoattractant Proteins; Oral; PECAM1 gene; Paclitaxel; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Pluronics; Procedures; Proliferating; Proteins; Recommendation; Recurrence; Renal Replacement Therapy; Risk; Role; Safety; Scanning; Smooth Muscle Myocytes; Stenosis; T cell infiltration; Testing; Time; Tunica Adventitia; Vascular Patency; Vascular remodeling; Veins; Venous; chemokine receptor; comparison control; cost; cytokine; drug release kinetics; experimental study; fatty acid-binding proteins; immune cell infiltrate; improved; inhibitor; injured; innovation; light scattering; loss of function; migration; monocyte; monocyte chemoattractant protein 1 receptor; mortality; mouse model; nanoparticle; neutralizing antibody; novel therapeutics; protein expression; recruit; restenosis; small molecule inhibitor; tandem mass spectrometry; ultrasound; vascular injury

PROJECT SUMMARY/ABSTRACT In 2017, ~750K Americans were diagnosed with end-stage kidney disease (ESKD), which rises 3% yearly. 87% will have renal replacement therapy with hemodialysis (HD), with preferred vascular access through arteriovenous fistula (AVF). AVFs have ~62% year patency due to venous stenosis (VS) and neointimal hyperplasia (VNH) causing reduced blood flow and suboptimal HD which is treated with percutaneous transluminal angioplasty (PTA) at >$3B/yr. Monocyte and macrophage recruitment occurs to the injured vessel wall after PTA of stenotic arteriovenous fistulas (AVF) through increased expression of MCP-1 leading to VS/VNH. Bindarit is an oral selective inhibitor of MCP-1, - 2, and -3 and we encapsulated it in polylactic-co-glycolic acid (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (BN NP) for periadventitial delivery to the outflow vein to test in this proposal. Scanning electron microscope and dynamic light scattering were used to characterize the BN NP and control nanoparticles (NP C). Liquid chromatography with tandem mass spectrometry (LC-MS/MS) was used to study drug release kinetics. Immediately after PTA, in a murine model of AVF stenosis, BN NP or NP C was administrated to the periadventitia of outflow veins. Animals were sacrificed 3 and 21 days later for gene expression, histomorphometric, and immunohistochemical analyses. Doppler ultrasound was performed weekly. There was no difference in the size and storage modulus of BN NP compared controls. Pharmacokinetic analysis demonstrated increased drug release from BN NP when compared to controls. BN NP treated vessels had reduced MCP-1, MCP-2 and MCP-3 gene and protein levels, reduced CCR2, increased FABP4/IL8, macrophage/monocyte abundance, proinflammatory cytokines, reduced CD4 (+) cells, reduced endothelial inflammation, and venous fibrosis resulting in positive vascular remodeling and improved patency with reduced VS/VNH. There was increased peak velocity 21 days after PTA in the BN NP group. Periadventitial administration of BN NP to the outflow vein after PTA results in decreased VS/VNH. Central Hypothesis. Periadventitial delivery of Bindarit NPs to AVF outflow vein after PTA decreases Mcp-1, -2, -3, CCR2 expression with increased FABP4/IL8 leading to less immune, macrophage cell infiltration with reduction in smooth muscle cells, fibrosis, and VS/VNH. We propose three specific aims: Aim 1: Determine how Bindarit NPs reduce MCP-1, -2, and -3 leading to decreased monocyte to macrophage differentiation, migration, proliferation, leukocyte chemoattraction by endothelial cells and inflammatory cytokine expression. Aim 2: Assess the role(s) of Bindarit NPs on CCR2 and FABP4/IL8 on reducing VS/VNH after PTA of stenotic AVFs. Aim 3: Ascertain the safety and efficacy of Bindarit NPs on reducing VS/VNH after PTA in pigs with CKD.

项目摘要/摘要 2017年，约75万美国人被诊断出患有终末期肾病(ESKD)，这一数字每年上升3%。87%的人会 接受血液透析(HD)的肾脏替代治疗，首选通过动静脉瘘进行血管通路 (AVF)。动静脉瘘由于静脉狭窄(VS)和新生内膜增生(VNH)导致的~62%的年通畅率 血流量减少和HD不理想，需要每年30亿美元的经皮腔内血管成形术(PTA)治疗。 狭窄动静脉瘘PTA术后损伤血管壁单核细胞和巨噬细胞的募集 (AVF)通过MCP-1表达增加导致VS/VNH。Bindarit是一种口服MCP-1选择性抑制剂，- 2和-3，我们将其包裹在聚乳酸-羟基乙酸(PLGA)纳米颗粒中，嵌入在热敏材料中 Pluronic F127水凝胶(BN NP)用于外膜外给药到流出静脉，以在这一建议中进行测试。正在扫描 用电子显微镜和动态光散射对BN-NP和对照纳米粒(NP)进行了表征 c)。采用LC-MS/MS联用技术研究药物释放动力学。 PTA后即刻，在AVF狭窄的小鼠模型中，外膜周围注射BN NP或NP C 流出的静脉。动物在3天和21天后被处死，进行基因表达、组织形态计量学和 免疫组织化学分析。每周进行一次多普勒超声检查。大小和大小没有差异 BN-NP的储能模数与对照组比较。药代动力学分析显示药物释放增加。 与对照组相比，BN NP。BN NP处理的血管减少了MCP-1、MCP-2和MCP-3的基因和蛋白 水平，降低CCR2，增加FABP4/IL8，巨噬细胞/单核细胞丰度，促炎细胞因子， CD4(+)细胞减少，内皮炎症减轻，静脉纤维化导致积极的血管重塑 VS/VNH降低，通畅性提高。在PTA后第21天，BN NP的峰值速度增加 一群人。PTA术后向流出静脉外膜注射BN-NP可降低VS/VNH。 中心假说。经皮腔内成形术(PTA)后外膜外膜注射Bindarit NPs至AVF流出静脉可降低MCP-1，-2，-3， CCR2表达增加，FABP4/IL8增加，导致免疫功能减弱，巨噬细胞浸润减少 平滑肌细胞、纤维化和VS/VNH。我们提出三个具体目标： 目的1：确定Bindarit NPs如何减少MCP-1、-2和-3，导致单核细胞/巨噬细胞减少 内皮细胞的分化、迁移、增殖、白细胞趋化与炎症 细胞因子的表达。 目的：评价CCR2和FABP4/IL8上的Bindarit NPs(S)在降低狭窄动静脉动静脉瘘PTA术后VS/VNH中的作用。 目的：探讨Bindarit纳米粒降低慢性肾脏病猪PTA术后VS/VNH的安全性和有效性。