Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula

预防动静脉瘘成熟失败的新分子靶点

• 批准号: 10457852
• 负责人: Devendra K. Agrawal
• 金额: $ 70.5万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457852
• 关键词: Accounting; Anatomy; Angiography; Antibodies; Apoptosis; Arterial Occlusive Diseases; Arteriovenous fistula; Autologous; Biological; Blood; Blood Vessels; Blood flow; Calcitriol; Caliber; Carotid Arteries; Cathepsin L; Cells; Chronic Kidney Failure; Collagen; Color; Data; Defect; Development; Doppler Ultrasound; Elastases; Elastin; Failure; Family suidae; Femoral vein; Fibrosis; Fistula; Functional disorder; Gene Expression; Growth Factor; HMGB1 gene; Hemodialysis; Histology; Human; Hyperplasia; IL8 gene; Immunology; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Kidney Failure; Knowledge; Lentivirus Vector; Leukocytes; Link; MME gene; Matrix Metalloproteinases; Measures; Mediating; Mediator of activation protein; Modeling; Molecular Biology; Molecular Target; Morbidity - disease rate; Myeloid Cells; Myofibroblast; Nephrology; Nitroglycerin; Operative Surgical Procedures; Optical Coherence Tomography; Outcome; Pathology; Patients; Peptides; Phase I Clinical Trials; Phenotype; Placebos; Proteins; Research; Sirolimus; Site; Smooth Muscle Myocytes; Stenosis; TLR4 gene; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tumor-infiltrating immune cells; Vascular Smooth Muscle; Vascular remodeling; Veins; Venous; antagonist; base; bevacizumab; cell motility; coronary artery occlusion; cytokine; design; experience; experimental group; extracellular; femoral artery; hemodynamics; iliac artery; improved; inhibitor; macrophage; migration; monocyte; mortality; neutrophil; new therapeutic target; novel; porcine model; prevent; receptor; response; vascular smooth muscle cell proliferation

ABSTRACT Autologous arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis. However, high rate of maturation failure due to inadequate blood flow in the outflow vein renders the fistula not useful for hemodialysis. Neointimal hyperplasia and failure of outward remodeling are the major causes of AVF maturation failure which is due to inflammation, proliferation, migration, and phenotypic changes of vascular smooth muscle cells (VSMCs), and extracellular remodeling due to increased matrix metalloproteinases (MMPs). We discovered increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1), TLR4 and related proteins in the immature AV fistula. Based on our novel findings, the central hypothesis is that hemodynamic injury during AVF creation induces inflammation to upregulate TREM-1 and TLR4 to enhance neointimal hyperplasia and vascular remodeling, and antagonizing TREM-1 and TLR4 will enhance AVF maturation. This hypothesis will be tested with the following Aims: Aim 1: Our corollary hypothesis predicts that the administration of TREM-1 and TLR4 antagonists will prevent maturation failure of AVF in swine. We will examine the effect of a potent inhibitory TREM-1 peptide in the AVF model in pigs. Since TREM-1 could synergize with TLR4 to mediate the pathology of AVF maturation failure, effect of a potent TLR4 antagonist will also be examined to prevent maturation failure of AVF. The outcome parameters will include neointimal hyperplasia in the inflow and outflow segments in the AVF, angiography of the AVF, color Doppler ultrasound, optical coherence tomography, and histology, immunostaining to analyze inflammation, expression of various mediators and infiltration of macrophages and neutrophils, VSMC apoptosis, and vascular remodeling. Aim 2: Our corollary hypothesis predicts that the TREM-1 and TLR4 antagonism inhibits inflammation and thus prevents maturation failure of AVF by reducing the development of intimal hyperplasia and vascular remodeling primarily due to inflammatory cells, cathepsin L, IL-8 and MMP-12. These studies will be performed in the blood and isolated VSMCs of femoral artery and femoral vein of the pigs from Aim 1. Mechanistic studies will examine the effect of TREM-1 and TLR4 inhibition in the presence of IL-8 on neutrophils, monocyte-differentiated macrophages and VSMCs, and cathepsin L-mediated elastin and collagen degradation in VSMCs, and the effect of elastin-derived peptides on monocyte differentiation into macrophages and VSMC proliferation and migration. Additional mechanistic studies will include the link between TLR4 and TREM-1 in promoting matrix remodeling, release of inflammatory cytokines from neutrophils and macrophages in the cross- talk inducing phenotype switch in VSMCs and macrophage polarization. The findings from this study will confirm if TREM-1 is a novel target for therapeutic intervention and extend the knowledge to develop better molecules to antagonize TREM-1 and design phase I clinical trials.

抽象的 自体动脉瘘（AVF）是血液透析中首选的血管通道。但是，高率 流出静脉流动不足导致的成熟失败使瘘管对血液透析无用。 新内膜增生和向外重塑的失败是AVF成熟失败的主要原因 是由于炎症，增殖，迁移和血管平滑肌细胞的表型变化 （VSMC）和由于基质金属蛋白酶（MMP）增加而引起的细胞外重塑。我们发现了 在髓样细胞1（TREM-1），TLR4和相关蛋白上表达的触发受体的表达增加 在未成熟的AV瘘中。根据我们的新发现，中心假设是血液动力学损伤 在AVF创建期间，诱导炎症上调TREM-1和TLR4以增强新内膜 增生和血管重塑，拮抗TREM-1和TLR4将增强AVF的成熟。 该假设将以以下目的进行检验：目标1：我们的推论假设预测 施用TREM-1和TLR4拮抗剂将防止AVF在猪中的成熟失败。我们将 检查猪在AVF模型中有效抑制性TREM-1肽​​的效果。因为Trem-1可以 与TLR4协同介导AVF成熟失败的病理，有效的TLR4拮抗剂的作用将 还可以检查以防止AVF的成熟失败。结果参数将包括新的 在AVF，AVF的血管造影，彩色多普勒超声的AVF的流入和流出段中的增生， 光学相干断层扫描和组织学，免疫染色以分析炎症，各种表达 巨噬细胞和中性粒细胞，VSMC凋亡和血管重塑的介体和浸润。目标2： 我们的推论假设预测，TREM-1和TLR4拮抗作用会抑制炎症，从而抑制 通过减少内膜增生和血管的发展来防止AVF的成熟失败 重塑主要是由于炎性细胞，组织蛋白酶L，IL-8和MMP-12。这些研究将是 从AIM 1中进行股动脉和股静脉的血液和分离的VSMC进行。 机械研究将检查IL-8存在对中性粒细胞的抑制作用， 单核细胞分化的巨噬细胞和VSMC，以及组织蛋白酶L介导的弹性弹性蛋白和胶原蛋白降解 在VSMC中，以及弹性蛋白衍生的肽对单核细胞分化为巨噬细胞和VSMC的影响 扩散和迁移。其他机械研究将包括TLR4和TREM-1之间的联系 促进基质重塑，从中性粒细胞和巨噬细胞中释放炎性细胞因子 在VSMC和巨噬细胞极化中诱导表型转换。 这项研究的发现将确认TREM-1是否是治疗干预的新目标并扩展 开发更好分子以对抗TREM-1和设计I期临床试验的知识。

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