Mechanism of Dialysis Arteriovenous Fistula Dysfunction

透析动静脉内瘘功能障碍的机制

基本信息

批准号：
7341127
负责人：
KARL A. NATH
金额：
$ 32.21万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-02-03 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341127
关键词：
Accounting Address Adoptive Cell Transfers Anti-Inflammatory Agents Anti-inflammatory Arteriovenous fistula Blood Vessels Bone Marrow Bone Marrow Transplantation CCL2 gene Cardiovascular system Caring Catheters Cell Proliferation Cells Clinical Dialysis procedure Disease Enzymes Failure Family suidae Fistula Functional disorder Heart Hypertrophy Hemodialysis Histologic Hospitalization Hyperplasia Immunophenotyping Impaired health Injury Interruption Investigation Kidney Diseases Kidney Failure Light Limb structure Literature Modeling Monocyte Chemoattractant Protein-1 Monocyte Chemoattractant Proteins Morbidity - disease rate Mus Nephrology Numbers Operative Surgical Procedures Pathogenesis Patient Care Patients Physical Dialysis Principal Investigator Process Rattus Relative (related person)Risk Factors Role Smooth Muscle Myocytes Stenosis Study models Thrombosis Time Up-Regulation Vascular remodeling Venous angiogenesis base chemokine clinically relevant cost directed attention heme a heme oxygenase-1 neointima formation neutralizing antibody prevent progenitor programs receptor role model

项目摘要

DESCRIPTION (provided by applicant): Hemodialysis vascular access dysfunction is considered the single most important issue in the care of the patient with endstage renal failure. Yet our understanding of the pathogenesis of vascular access dysfunction is poor, to a large extent, because of the lack of availability of relevant models amenable to investigation. The PI has demonstrated that the venous limb of an aorto-caval fistula in the rat recapitulates changes seen in dysfunctional dialysis arteriovenous fistulae (AVFs): neointima formation, angiogenesis, thrombosis, smooth muscle cell proliferation, and matrix expansion; these changes in this model are preceded by massive upregulation of MCP-1 (monocyte chemoattractant protein-1), the latter being one of the most important chemokines in vascular injury, and an independent risk factor for the dysfunction of clinical AVFs. MCP-1 can be downregulated by mechanisms which include heme oxygenase-1 (HO-1), a heme-degrading, vasoprotective, and anti-inflammatory enzyme. This application examines the significance of MCP-1 upregulation in this AVF model, and whether HO-dependent strategies can inhibit MCP-1 and intimal hyperplasia. Aim I hypothesize that, and examine whether, clinically relevant mechanisms account for MCP-1 upregulation and intimal hyperplasia. Aim II hypothesizes that MCP-1 upregulation is a determinant of intimal hyperplasia, and employs strategies which interrupt MCP-1 or its receptor. Aim III determines whether HO induction or specific HO products/effectors inhibit MCP-1 expression and intimal hyperplasia. Aim IV hypothesizes that venous remodeling in the AVF involves MCP-1-dependent recruitment of circulating and bone marrow-derived cells, and analyzes the origin of cells in the AVF by immunophenotyping, bone marrow transplantation, and adoptive cell transfer. In aggregate, these studies will determine the basis for and the pathogenetic significance of such upregulation of MCP-1, and may suggest strategies for preventing dysfunction of AVFs.

描述（由申请人提供）：血液透析血管通路功能障碍被认为是终末期肾衰竭患者护理中最重要的问题。然而，我们对血管通路功能障碍的发病机制的了解很差，很大程度上是因为缺乏适合研究的相关模型。 PI 证明，大鼠主动脉腔静脉瘘的静脉肢重现了功能障碍性透析动静脉瘘 (AVF) 中所见的变化：新内膜形成、血管生成、血栓形成、平滑肌细胞增殖和基质扩张；该模型中的这些变化先于 MCP-1（单核细胞趋化蛋白-1）的大量上调，后者是血管损伤中最重要的趋化因子之一，也是临床 AVF 功能障碍的独立危险因素。 MCP-1 可通过血红素加氧酶-1 (HO-1) 等机制下调，血红素氧化酶是一种血红素降解酶、血管保护酶和抗炎酶。本申请检验了 MCP-1 上调在此 AVF 模型中的重要性，以及 HO 依赖性策略是否可以抑制 MCP-1 和内膜增生。目的我假设并检验临床相关机制是否能解释 MCP-1 上调和内膜增生。 Aim II 假设 MCP-1 上调是内膜增生的决定因素，并采用干扰 MCP-1 或其受体的策略。目标 III 确定 HO 诱导或特定 HO 产品/效应物是否抑制 MCP-1 表达和内膜增生。 Aim IV 假设 AVF 中的静脉重塑涉及循环细胞和骨髓来源细胞的 MCP-1 依赖性募集，并通过免疫表型、骨髓移植和过继性细胞转移分析 AVF 中细胞的起源。总的来说，这些研究将确定 MCP-1 上调的基础和发病意义，并可能提出预防 AVF 功能障碍的策略。