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

• 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
• 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

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 目前，美国有70多万名终末期肾病(ESRD)患者。 约70%的终末期肾病患者以血液透析为主要肾脏 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%创建的AVF会发生AVF成熟失败 由于早期静脉新生内膜增生形成和外向血管受损 改建。AVF成熟失败的病理机制尚不清楚。 明白了。因此，该领域一个主要的未得到满足的临床需求是缺乏有效的 治疗和预防动静脉瘘成熟失败的治疗方法。这项研究的中心假设是 AVF的产生将导致一氧化氮(NO)和cGMP活性的失调，从而 通过影响aVF重构和新生内膜增生来干扰aVF的正常成熟 队形。因此，NO/cGMP信号通路是骨肉瘤治疗的重要靶点。 临床成功的动静脉动静脉瘘成熟。目的：探讨NO和cGMP在房颤发生中的作用。 我们将1)检验在动静脉瘘发生时局部未给予治疗的假设。 创造将通过抑制新生内膜增生和增强AVF来促进AVF的成熟 重塑，并减少局部炎症；2)检验选择性PDE5A 可防止cGMP降解的抑制剂，在AVF创建之前和之后使用，将 改善AVF外向重构，抑制新生内膜增生，也将是有益的 在慢性肾脏疾病(CKD)的背景下，动静脉瘘是在这种临床背景下产生的。 这些目标将使用啮齿动物AVF模型来实现，该模型具有(1)相同的解剖结构 人动静脉瘘的构型和(2)累及静脉新生内膜病变的情况 人动静脉瘘可见增生性病变。我们的研究有望阐明 NO/cGMP信号通路在动静脉动静脉瘘成熟过程中的意义 开发新的治疗策略来治疗和预防血液透析中AVF成熟失败 病人。