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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：
10209194
负责人：
TIMMY C LEE
金额：
$ 59.41万
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/10209194
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 Ultrasonography 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

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.

血管通道是血液透析患者的生命线，也是最重要的生命线