Mechanism of Dialysis Arteriovenous Fistula Dysfunction

描述（由申请人提供）：血液透析血管通路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了解甚少，这在很大程度上是因为缺乏可用于研究的相关模型。PI显示，大鼠主动脉-腔静脉瘘的静脉肢重现了功能障碍透析动静脉瘘（AVFs）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；这些变化发生在MCP-1（单核细胞趋化蛋白-1）大量上调之前，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的下调机制包括血红素加氧酶-1 (HO-1)，一种血红素降解、血管保护和抗炎酶。本应用检验了MCP-1上调在AVF模型中的意义，以及ho依赖策略是否能抑制MCP-1和内膜增生。目的：假设MCP-1上调和内膜增生是否与临床相关。Aim II假设MCP-1上调是内膜增生的决定因素，并采用阻断MCP-1或其受体的策略。目的III确定HO诱导或特定HO产物/效应器是否抑制MCP-1表达和内膜增生。目的IV假设AVF中的静脉重构涉及循环细胞和骨髓来源细胞的mcp -1依赖性募集，并通过免疫分型、骨髓移植和过继细胞移植分析AVF中细胞的来源。综上所述，这些研究将确定MCP-1上调的基础和病理意义，并可能为预防avf功能障碍提供策略。

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.