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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要