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Autophagy and Arteriovenous Fistula Maturation

自噬和动静脉瘘成熟

基本信息

批准号：
10412012
负责人：
TIMMY C LEE
金额：
$ 53.85万
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：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10412012
关键词：
Address Anastomosis - action Arteriovenous fistula Atherosclerosis Autophagocytosis Autophagosome Blood Vessels Blood flow Caliber Catheters Chronic Kidney Failure Clinical Coculture Techniques Cultured Cells Custom Data Development Dialysis procedure End stage renal failure Endothelial Cells Endothelium Etiology Failure Fistula Functional disorder Generations Goals Harvest Hemodialysis Histologic Homeostasis Human Hyperplasia In Vitro Innovative Therapy Knockout Mice Knowledge Lysosomes Mediating Mission Morbidity - disease rate Mus NOS3 gene Nitric Oxide Organelles Outcome Pathogenesis Pathologic Pathology Patients Perfusion Play Procedures Process Proteins Public Health Radiology Specialty Repression Research Resources Role Serum Signal Pathway Smooth Muscle Myocytes Stenosis System Testing Umbilical vein United States United States National Institutes of Health Vasodilation Veins Venous Work base biobank clinically relevant effective therapy exposed human population hemodynamics human disease improved in vivo mortality novel novel therapeutics porcine model preservation prevent response therapeutic target tool ultrasound

项目摘要

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.

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。