Autophagy and Arteriovenous Fistula Maturation

血管通路是血液透析患者的生命线， 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内瘘（AVF）未能成熟 成功用于透析（AVF成熟失败）。目前，仍有很高的 在美国，AVF成熟失败，并且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，其特征在于 内膜增生和向外重塑不良。AVF后的不良结局 创建反映了我们对导致AVF成熟失败的机制的有限理解;以及 治疗这种临床问题的疗法的缺乏代表了未满足的临床需求。的目标 本研究旨在探索一种新的模式，即自噬在AVF成熟中的作用。我们 该提案是新颖的，并得到了我们研究团队的有力初步工作的支持， 抑制内皮细胞（EC）自噬在AVF成熟失败中的因果作用， AVF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，该建议的中心假设是扰动流 CKD抑制内皮细胞自噬，导致AVF成熟失败。结合使用 在体外、体内和人体研究中，我们将以三个具体目标来检验我们的中心假设：（1） 确定EC自噬抑制的步骤，在扰动流和CKD环境的设置，（2）定义 抑制EC自噬如何促进AVF重塑，以及（3）确定 自噬在血液透析患者AVF成熟中的作用我们相信我们的研究计划 意义重大，因为：（1）它解决了血液透析患者中一个非常重要的临床问题，AVF 成熟失败，目前没有有效的治疗方法;（2）检查新的 AVF发展的范例，自噬。成功完成这些目标将确定 开发创新疗法的重要目标，旨在改变自噬， 促进AVF成熟。

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.