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：
9910167
负责人：
Maheshika Somarathna
金额：
$ 3.83万
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/9910167
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 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.

项目摘要目前，美国有超过700,000个末期肾病（ESRD）患者。大约70％的ESRD患者接受血液透析为主要肾脏替代疗法。动静脉瘘（AVF）是首选的血管通道血液透析患者。但是，将近60％的AVF创建了AVF成熟失败由于早期的静脉新内膜增生形成和外部血管受损重塑。 AVF成熟失败的基础病理机制很差理解。因此，该领域的主要未满足临床需求是缺乏有效治疗和防止AVF成熟失败的疗法。这项研究的中心假设是该AVF的创建将导致一氧化氮（NO）和CGMP活性的失调通过影响AVF重塑和新内膜增生来破坏适当的AVF成熟形成。因此，没有/CGMP信号通路是重要的治疗靶点临床上成功的AVF成熟。为了研究NO和CGMP对AVF的作用成熟度我们将1）检验以下假设，即AVF时局部未提供任何治疗创建将通过抑制新内膜增生并增强AVF来改善AVF的成熟重塑并减少局部炎症； 2）检验选择性PDE5A的假设防止CGMP降解的抑制剂在创建AVF之前和之后进行管理，将改善AVF向外重塑并抑制新的增生；并且也将是有益的在慢性肾脏疾病（CKD）的环境中，在这种临床环境中创建了AVF。这些目标将使用具有（1）相同解剖学的啮齿动物AVF模型来实现对人AVF的构型，（2）概括进行性静脉疾病的病变在人AVF中看到的增生。我们的研究有望阐明病理学 NO/CGMP信号通路对AVF成熟的重要性，并提供了基础制定新的治疗策略来治疗和预防血液透析中的AVF成熟衰竭患者。