Autophagy and Arteriovenous Fistula Maturation

血管通路是血液透析患者的生命线，也是最重要的一条 血液透析程序的组成部分。血管通路最常见的病因 血液透析患者的功能障碍是动静脉瘘(AVF)不成熟 成功用于透析(AVF成熟失败)。目前，仍有很高的比率 AVF在美国的成熟失败，目前还没有有效的治疗方法来增强AVF 成熟。在放射学水平上，aVF成熟失败最常见的特征是 静脉吻合口狭窄，在组织学水平上表现为 侵袭性内膜增生和不良外在重塑。动静脉动静脉瘘的不良结局 创造反映了我们对AVF成熟失败的机制的有限理解；以及 缺乏治疗这一临床问题的疗法代表着一种未得到满足的临床需求。的目标是 这一建议是为了研究一种新的范式，即自噬在AVF成熟过程中的作用。我们的 提案是新颖的，并得到了我们研究团队强有力的前期工作的支持，指出 抑制内皮细胞(EC)自噬在AVF成熟失败中的作用 动静脉瘘和慢性肾脏疾病(CKD)环境中血流动力学紊乱的独特环境。 基于这些初步研究，这一提议的中心假设是扰动流动 CKD抑制血管内皮细胞自噬，导致AVF成熟失败。使用以下组合 在体外、体内和人体研究中，我们将以三个具体目标来测试我们的中心假设：(1) 确定扰动流和CKD环境中EC自噬抑制的步骤，(2)定义 抑制的EC自噬如何促进AVF重塑，以及(3)确定 血液透析患者动静脉瘘成熟过程中的自噬。我们相信我们提出的研究是 重要的是：(1)它解决了血液透析患者的一个非常重要的临床问题--动静脉瘘 成熟失败，目前没有有效的治疗方法；和(2)检查新的 AVF发展中的范例，自噬。成功完成这些目标将确定 开发旨在改变自噬的创新疗法的重要目标 增强AVF的成熟度。

The vascular access is the lifeline for the hemodialysis patient and the single most important component of the hemodialysis procedure. The most common etiology of vascular access dysfunction in hemodialysis patients is failure of an arteriovenous fistula (AVF) to mature successfully for dialysis use (AVF maturation failure). At present, there remains a very high rate of AVF maturation failure in the United States and there are no effective treatments to enhance AVF maturation. On a radiologic level, AVF maturation failure is most commonly characterized by a stenosis at the venous anastomosis, and at a histological level it is characterized by a combination of aggressive intimal hyperplasia and poor outward remodeling. The poor outcomes following AVF creation reflect our limited understanding of the mechanisms leading to AVF maturation failure; and the lack of therapies to treat this clinical problem represent an unmet clinical need. The objective of this proposal is to investigate a new paradigm, the role of autophagy in AVF maturation. Our proposal is novel and supported by strong preliminary work from our research team pointing to a causal role for repressed endothelial cell (EC) autophagy in AVF maturation failure, in response to a unique setting of disturbed hemodynamics in the AVF and chronic kidney disease (CKD) milieu. Based on these preliminary studies, the central hypothesis of this proposal is that disturbed flow and CKD repress endothelial autophagy, leading to AVF maturation failure. Using a combination of in vitro, in vivo, and, human studies, we will test our central hypothesis with three specific aims: (1) Identify steps of EC autophagy repression in the setting of disturbed flow and CKD milieu, (2) Define how repressed EC autophagy contributes to AVF remodeling, and (3) Determine the role of autophagy in AVF maturation in hemodialysis patients. We believe our proposed research is significant because: (1) it addressed a very important clinical problem in hemodialysis patients, AVF maturation failure, where there are presently no effective therapies; and (2) examine a new paradigm in AVF development, autophagy. Successful completion of these aims will identify important targets for developing innovative therapies that aim to modify autophagy in order to enhance AVF maturation.