Autophagy and Arteriovenous Fistula Maturation

自噬和动静脉瘘成熟

• 批准号: 10614597
• 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
• 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/10614597
• 关键词: Address; Anastomosis - action; Arteriovenous fistula; Atherosclerosis; Autophagocytosis; Autophagosome; Blood Vessels; Blood flow; Catheters; Chronic Kidney Failure; Clinical; Coculture Techniques; Cultured Cells; Data; Development; Dialysis procedure; Diameter; 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; 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

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，也是最重要的通道 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）未能成熟 成功用于透析（AVF 成熟失败）。目前，仍然有很高的比例 美国 AVF 成熟失败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 静脉吻合处的狭窄，在组织学水平上，其特点是结合 侵袭性内膜增生和不良的外向重塑。 AVF 术后不良后果 创作反映了我们对导致 AVF 成熟失败的机制的有限理解；和 缺乏治疗这一临床问题的疗法代表了未满足的临床需求。的目标 该提案旨在研究一种新的范式，即自噬在 AVF 成熟中的作用。我们的 该提案是新颖的，并得到我们研究团队强有力的初步工作的支持，指出 抑制内皮细胞（EC）自噬在 AVF 成熟失败中的因果作用，响应 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，该提案的中心假设是扰动流 CKD 抑制内皮自噬，导致 AVF 成熟失败。使用组合 在体外、体内和人体研究中，我们将通过三个具体目标来检验我们的中心假设：(1) 确定在血流紊乱和 CKD 环境中 EC 自噬抑制的步骤，(2) 定义 受抑制的 EC 自噬如何促进 AVF 重塑，以及 (3) 确定 血液透析患者 AVF 成熟过程中的自噬。我们相信我们提出的研究是 意义重大，因为：（1）它解决了血液透析患者的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) 检验一个新的 AVF 发育的范例，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 成熟度。

项目成果

Biomimetic cardiac tissue chip and murine arteriovenous fistula models for recapitulating clinically relevant cardiac remodeling under volume overload conditions.

• DOI: 10.3389/fbioe.2023.1101622
• 发表时间: 2023
• 期刊: FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
• 影响因子: 5.7
• 作者: Waldrop, Tatyana Isayeva;Graham, Caleb;Gard, William;Ingle, Kevin;Ptacek, Travis;Nguyen, Nguyen;Lose, Bailey;Sethu, Palaniappan;Lee, Timmy
• 通讯作者: Lee, Timmy