Basic mechanisms in arteriovenous fistula maturation for hemodialysis

血液透析动静脉内瘘成熟的基本机制

• 批准号: 8391101
• 负责人: Eugene Sangkeu Lee
• 金额: --
• 依托单位: VA NORTHERN CALIFORNIA HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391101
• 关键词: Adhesions; Affect; Animal Model; Area; Arteriovenous fistula; Biological Assay; Biological Markers; Biometry; Blood; Blood Cells; Blood Flow Velocity; Blood Vessels; Blood flow; Caring; Case Report Form; Catheters; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cells; Clinical Trials; Coupled; Data; Diabetes Mellitus; Dialysis patients; Dialysis procedure; Doctor of Philosophy; End stage renal failure; Endothelial Cells; Environment; Epidemic; Failure; Fellowship; Fistula; Forearm; Foundations; Functional disorder; Gelatinases; Goals; Grant; Growth; Growth Factor; Guidelines; Hemodialysis; Human; Hyperplasia; Hypertension; Incidence; Infection; Infiltration; Inflammatory; Injury; Intervention; Kidney; Kidney Diseases; Kidney Failure; Lead; Leukocytes; Maintenance; Manuscripts; Matrix Metalloproteinases; Measurement; Medical; Medical center; Molecular; Molecular Target; Multivariate Analysis; National Research Service Awards; Obesity; Operative Surgical Procedures; Outcome; Pathologic; Pathology; Patient Care; Patients; Peer Review; Permeability; Population; Prevalence; Procedures; Process; Production; Proteins; Publications; Publishing; Regulation; Repeat Surgery; Research; Research Training; Resistance; Risk Factors; Role; Stenosis; Surgeon; Surgical Injuries; Survival Analysis; Techniques; Testing; Thick; Thrombosis; Training Programs; Ultrasonography; United States Centers for Medicare and Medicaid Services; United States National Institutes of Health; Vascular remodeling; Veins; Venous; Veterans; Western Blotting; Work; abstracting; base; career; cost; cytokine; electric impedance; improved; insight; interest; intima media; migration; monocyte; mortality; novel diagnostics; peripheral blood; response; shear stress; stem; success; tool; translational approach; vascular inflammation

DESCRIPTION (provided by applicant): Project Summary/Abstract NOMINEE: This proposal describes a three year training program to develop a candidate's academic career in Vascular Surgery centered at a VA medical center. The candidate spent 3 years in formal research training at the Minneapolis VA with an NIH F32 NRSA fellowship grant working on intimal hyperplasia, a pathologic form of vascular remodeling after surgical injury. From the fellowship, the candidate published 15 peer-reviewed publications, 8 as first author and 6 directly related to the NRSA project. The fellowship led to the successful defense of a PhD thesis. The candidate has continued his research interests through a translational approach to vascular remodeling assessing the mechanisms of vein remodeling after arteriovenous fistula (AVF) construction for renal failure patients. In the past year, the candidate has published 3 peer-reviewed manuscripts related to this area, 1 as first author. HYPOTHESIS: The candidate plans to test the hypothesis that monocyte-endothelial cell adhesion followed by transmigration induces endothelial barrier injury and impairs Matrix Metalloproteinase (MMP) production and activity, leading to the failure of AVF maturation. SPECIFIC OBJECTIVES: (1) To evaluate the biomarker role of MMPs and monocyte adhesion molecules in the blood and vein segment of hemodialysis patients for predicting AVF maturation. (2) To investigate the molecular mechanisms of monocyte-endothelial cell interactions in endothelial barrier dysfunction and MMP dysregulation, leading to fistula failure. RELEVANCE: A vascular procedure where failure is more common (30-60% failure rate) than success is the surgical construction of a mature autogenous AVF for hemodialysis access. This project emphasizes the interactive roles of blood cells and endothelial cells in vascular injury, with a practical view on the identification of new diagnostic tools and molecular targets for improved AVF outcome. SUBJECT POPULATION: All Veteran patients with renal insufficiency or renal failure. PROCEDURES TO BE USED: Molecular analyses will be performed in vein segments and blood from patients undergoing hemodialysis access surgery. The following experimental procedures will be used to test the stated hypothesis: 7 Isolation and purification of monocyte isolation from peripheral blood. 7 Gelatinase zymography and Western immunoblot quantification of protein (MMPs) expression. 7 Flow cytometric measurement of adhesion molecules 7 Electric Cell-substrate Impedance Sensing (ECIS) technique 7 Transwell assays of monocyte transendothelial migration and endothelial permeability 7 Biostatistics: Multivariate analysis and survival analysis (vein maturation and duration) 7 Patient management and case report form management. SIGNIFICANCE OF POTENTIAL NEW FINDINGS: Important insight can be gained in describing the mechanism for vein remodeling after AVF construction. If reliable biomarkers can be developed, certain patients could potentially be selected for alternative hemodialysis access such as a primary bridge graft. Furthermore, greater insight into the mechanism could lead to clinical trials evaluating medical therapies that decrease monocyte-endothelial cell interactions, such as statins. If successful, maturation rates for AVF would improve and the need for repeat surgery minimized.

描述（由申请人提供）： 项目概要/摘要提名：本提案描述了一个为期三年的培训计划，以发展候选人的学术生涯在血管外科为中心的VA医疗中心。该候选人在明尼阿波利斯VA接受了3年的正式研究培训，获得了NIH F32 NRSA奖学金，研究内膜增生，这是手术损伤后血管重塑的一种病理形式。候选人利用研究金发表了15篇同行评审的出版物，其中8篇是第一作者，6篇与NRSA项目直接相关。该奖学金导致了博士论文的成功答辩。该候选人通过血管重塑的转化方法继续他的研究兴趣，评估肾衰竭患者动静脉瘘（AVF）构建后静脉重塑的机制。在过去的一年里，候选人发表了3篇与该领域相关的同行评审手稿，其中1篇是第一作者。假设：候选人计划检验以下假设：单核细胞-内皮细胞粘附，随后迁移诱导内皮屏障损伤并损害基质金属蛋白酶（MMP）的产生和活性，导致AVF成熟失败。具体说明：（1）探讨MMPs和单核细胞粘附分子在血液透析患者血液和静脉段中预测AVF成熟的生物标志物作用。(2)探讨单核细胞-内皮细胞相互作用在内皮屏障功能障碍和MMP失调中导致内瘘失败的分子机制。相关性：失败率（30-60%）高于成功率的血管手术是手术构建成熟自体AVF用于血液透析通路。该项目强调了血细胞和内皮细胞在血管损伤中的相互作用，并对识别新的诊断工具和改善AVF结局的分子靶点提出了实用的观点。亚组人群：所有肾功能不全或肾衰竭退伍军人患者。待用程序：将对接受血液透析通路手术的患者的静脉节段和血液进行分子分析。将使用以下实验程序来检验所述假设：7从外周血分离单核细胞的分离和纯化。7明胶酶谱和蛋白质（MMPs）表达的Western免疫印迹定量。7粘附分子的流式细胞术测量7电细胞基质阻抗传感（ECIS）技术7单核细胞跨内皮迁移和内皮通透性的Transwell测定7生物统计学：多变量分析和存活分析（静脉成熟和持续时间）7患者管理和病例报告表管理。潜在新发现的意义：在描述AVF构建后静脉重塑的机制方面可以获得重要的见解。如果能够开发出可靠的生物标志物，某些患者可能会被选择用于替代血液透析通路，例如一级桥接移植物。此外，对该机制的更深入了解可能导致临床试验评估减少单核细胞-内皮细胞相互作用的药物治疗，如他汀类药物。如果成功，AVF的成熟率将提高，重复手术的需要最小化。