Mechanism of Dialysis Arteriovenous Fistula Dysfunction

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功能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少，这在很大程度上是因为缺乏可供研究的相关模型。PI已证实，大鼠主动脉-下腔静脉瘘的静脉肢体概括了功能性透析性动静脉瘘(AVF)的变化：新生内膜形成、血管生成、血栓形成、平滑肌细胞增殖和基质扩张；在该模型中，这些变化之前伴随着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可通过包括血红素加氧酶-1(HO-1)在内的机制下调，HO-1是一种血红素降解、血管保护和抗炎酶。该应用研究了在该AVF模型中MCP-1上调的意义，以及HO依赖的策略是否可以抑制MCP-1和内膜增生。目的我假设MCP-1表达上调和内膜增生是否与临床相关的机制有关。目的II假设单核细胞趋化蛋白-1(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。目的确定HO诱导或特异性HO产物/效应物是否抑制单核细胞趋化蛋白-1(MCP-1)的表达和内膜增生。目的通过免疫表型、骨髓移植、过继细胞移植等方法分析动静脉瘘的细胞来源，提出动静脉瘘的静脉重构涉及单核细胞趋化蛋白-1(MCP-1)依赖的募集。总之，这些研究将确定单核细胞趋化蛋白-1上调的基础和发病意义，并可能提出预防动静脉瘘功能障碍的策略。

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.