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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.

项目概要目前美国有超过 700,000 名终末期肾病 (ESRD) 患者。大约 70% 的 ESRD 患者接受血液透析作为主要肾脏替代疗法。动静脉瘘 (AVF) 是血管通路的首选类型血液透析患者。然而，近 60% 的 AVF 出现 AVF 成熟失败由于早期静脉新生内膜增生形成和向外血管受损重塑。 AVF 成熟失败的病理机制尚不明确明白了。因此，该领域一个主要的未满足的临床需求是缺乏有效的治疗和预防 AVF 成熟失败的疗法。本研究的中心假设是 AVF 的产生将导致一氧化氮 (NO) 和 cGMP 活性失调，从而通过影响 AVF 重塑和新生内膜增生来破坏 AVF 的正常成熟形成。因此，NO/cGMP信号通路是一个重要的治疗靶点。临床上成功的 AVF 成熟。为了研究NO和cGMP对AVF的作用成熟后，我们将 1) 检验 AVF 时局部提供 NO 治疗的假设创造将通过抑制新内膜增生来改善 AVF 成熟并增强 AVF 重塑，减少局部炎症； 2) 检验选择性 PDE5A 的假设抑制剂，可防止 cGMP 降解，在 AVF 创建之前和之后施用，将改善AVF向外重塑并抑制新生内膜增生；并且也会有好处在慢性肾脏病 (CKD) 的情况下，在这种临床环境中创建 AVF。这些目标将通过使用啮齿动物 AVF 模型来实现，该模型具有 (1) 相同的解剖结构与人类 AVF 的配置和 (2) 概括了进行性静脉新内膜的病变人类 AVF 中可见增生。我们的研究有望阐明病理学 NO/cGMP信号通路对AVF成熟的意义以及为AVF成熟提供依据开发新的治疗策略来治疗和预防血液透析中 AVF 成熟失败患者。