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The Role of Nitric oxide/cyclic Guanosine Monophosphate (NO/cGMP) Signaling in Arteriovenous Fistula Maturation

一氧化氮/环磷酸鸟苷 (NO/cGMP) 信号在动静脉瘘成熟中的作用

基本信息

批准号：
10083108
负责人：
Maheshika Somarathna
金额：
$ 3.93万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2019-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083108
关键词：
Anastomosis - action Anatomy Arteries Arteriovenous fistula Biological Biological Assay Biological Availability Biological Markers Blood Vessels Blood flow Caliber Chronic Kidney Failure Clinical Cyclic GMP Development Dialysis procedure Doppler Ultrasound End stage renal failure Endothelial Cells Endothelium Failure Femoral vein Functional disorder Gel Goals Hemodialysis Human Hyperplasia Impairment Inflammation Inflammatory Injury Lesion Measures Microscopic Modeling Morbidity - disease rate NOS3 gene Nitric Oxide Oxidative Stress Pathologic Patients Physiologic arteriovenous anastomosis Play Procedures Rattus Relaxation Renal Replacement Therapy Rodent Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Soluble Guanylate Cyclase Sprague-Dawley Rats Testing Time Treatment Cost United States Uremia Vascular Smooth Muscle Vascular remodeling Venous Western Blotting Work cost design effective therapy endothelial dysfunction improved inhibitor/antagonist insight intimal medial thickening mortality novel therapeutic intervention novel therapeutics phosphoric diester hydrolase prevent response sildenafil therapeutic target

项目摘要

PROJECT SUMMARY There are currently over 700,000 end stage renal disease (ESRD) patients in the United States. Approximately 70% of ESRD patients undergo hemodialysis as their primary kidney replacement therapy. An arteriovenous fistula (AVF) is the preferred type of vascular access in hemodialysis patients. However, nearly 60% of AVFs created develop AVF maturation failure due to early venous neointimal hyperplasia formation and impaired outward vascular remodeling. The pathological mechanisms underlying AVF maturation failure is poorly understood. Therefore, a major unmet clinical need in the field is the lack of effective therapies to treat and prevent AVF maturation failure. The central hypothesis of this study is that AVF creation will result in dysregulation of nitric oxide (NO) and cGMP activity that will disrupt proper AVF maturation by influencing AVF remodeling and neointimal hyperplasia formation. Therefore, NO/cGMP signaling pathway is an important therapeutic target for clinically successful AVF maturation. In order to study the role of NO and cGMP on AVF maturation we will 1) test the hypothesis that locally delivered NO therapy at the time of AVF creation will improve AVF maturation by inhibiting neointimal hyperplasia and enhance AVF remodeling, and reduce local inflammation; 2) test the hypothesis that a selective PDE5A inhibitor, which prevents cGMP degradation, administered before and after AVF creation, will improve AVF outward remodeling and inhibit neointimal hyperplasia; and will be also beneficial in the setting of chronic kidney disease (CKD), where AVFs are created in this clinical setting. These aims will be achieved using a rodent AVF model that has (1) an identical anatomic configuration to human AVF and (2) recapitulates the lesion of progressive venous neointimal hyperplasia seen in human AVF. Our studies are expected to elucidate the pathologic significance of NO/cGMP signaling pathway on AVF maturation as well as provide the basis to develop novel therapeutic strategies to treat and prevent AVF maturation failure in hemodialysis patients.

项目总结