The Role of Vascular Calprotectin in Arteriovenous Fistula Maturation

血管钙卫蛋白在动静脉瘘成熟中的作用

• 批准号: 10609080
• 负责人: Roberto Irenardo Vazquez Padron
• 金额: $ 43.31万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609080
• 关键词: Age; American; Arteriovenous fistula; Automobile Driving; Basic Science; Biology; Blood Vessels; Blood flow; Catheters; Chronic Kidney Failure; Clinical; Data; Development; Dialysis patients; Dialysis procedure; Ectopic Expression; End stage renal failure; Experimental Animal Model; Failure; Fibrosis; Fistula; Functional disorder; Gene Expression; Genetic; Genetic Transcription; Goals; Hemodialysis; Human; Hyperplasia; Inflammation; Inflammatory; Injections; Intervention; Kidney Diseases; Knockout Mice; Lead; Legal patent; Leukocyte L1 Antigen Complex; Life; Mediating; Medical Care Costs; Microsurgery; Molecular; Morbidity - disease rate; Mus; Outcome; Outcome Study; Pathogenicity; Pathologic; Patient Selection; Patients; Phenotype; Postoperative Period; Publishing; Quality of life; Random Allocation; Research; Retrospective cohort; Risk; Role; SPI1 gene; Sampling; Secure; Signal Transduction; Smooth Muscle Myocytes; Stenosis; Stromal Cell-Derived Factor 1; Study models; Tamoxifen; Techniques; Testing; Translational Research; Up-Regulation; Validation; Venous; biobank; cell type; cohort; cost comparison; design; experience; improved; inhibitor; medical complication; mortality; new therapeutic target; novel therapeutics; prevent; proto-oncogene protein Spi-1; response; sex; systemic inflammatory response; targeted treatment

Over 600,000 Americans live with end-stage renal disease (ESRD), and ∼468,000 of them are dialysis patients who depend on a functional vascular access to extend their lives. A mature arteriovenous (A-V) fistula is the preferred dialysis access due to its higher patency rates and lower medical costs compared to synthetic grafts and central venous catheters. However, ~40% of newly created fistulas fail to mature, i.e., they are not usable for dialysis because stenosis prevents them from reaching the necessary blood flow. There is paucity of research into the mechanisms underlying postoperative stenosis in A-V fistulas, despite its negative impact on morbidity, mortality, and quality of life of these patients. This translational proposal establishes the mechanistic relationship among the CXCL12 and PU.1/calprotectin signaling network, inward remodeling, and fistula outcomes in order to design targeted therapies to prevent maturation failure. Our proposal is built on strong scientific premises that suggest a mechanistic relationship between postoperative accumulation of calprotectin in A-V fistulas caused by ectopic expression of the transcription factor PU.1 and inward remodeling that causes fistula failure. Our overarching hypothesis is that smooth muscle cell (SMC)-derived calprotectin increases the risk for stenosis and failure in newly created A-V fistulas. Our mechanistic hypothesis is that elevated CXCL12 level in hemodialysis patients leads to ectopic expression of PU.1 in the vasculature and the subsequent accumulation of calprotectin in SMCs. The released calprotectin exacerbates inflammation, fibrosis, and intimal hyperplasia (IH) after fistula creation. We will test our hypothesis in three specific aims and five experimental layouts that will prove: 1) the contribution of calprotectin to fistula inward remodeling; 2) the underlying mechanisms by which CXCL12 and PU.1 increases calprotectin and the risk of A-V fistula failure; and 3) the relationship between PU.1 and fistula maturation outcomes in a human cohort. We will combine fine microsurgical techniques and knockout mice to successfully achieve our goals. We will also interrogate a human biorepository of 100 randomly selected patients undergoing creation of two-stage brachiobasilic transposition fistulas to search for associations between the levels of PU.1 after venous remodeling and inadequate maturation. In conclusion, with the successful accomplishment of this proposal, we are paving the way for the design of new drugs and cell type-specific interventions to effectively target A-V fistula fibrosis and IH and reduce vascular access complications.

超过60万美国人患有终末期肾病（ESRD），其中46.8万人是透析患者，他们依赖功能性血管通路来延长生命。成熟的动静脉（A-V）瘘是首选的透析通路，因为与合成移植物和中心静脉导管相比，其通畅率更高，医疗成本更低。然而，约40%的新形成的瘘管未能成熟，即，它们不能用于透析，因为狭窄阻止它们到达必要的血流。尽管动静脉瘘术后狭窄对患者的发病率、死亡率和生活质量有负面影响，但对动静脉瘘术后狭窄的机制研究很少。该翻译提案建立了CXCL 12和PU.1/钙卫蛋白信号网络、内向重塑和瘘管结局之间的机制关系，以设计靶向治疗来预防成熟失败。我们的建议是建立在强有力的科学前提下，表明转录因子PU.1的异位表达引起的动静脉瘘中钙卫蛋白的术后积累与导致瘘失败的向内重塑之间存在机械关系。我们的总体假设是平滑肌细胞（SMC）衍生的钙卫蛋白增加了新创建的动静脉瘘狭窄和失败的风险。我们的机制假设是血液透析患者中CXCL 12水平升高导致PU.1在血管系统中的异位表达和随后的SMC中钙卫蛋白的积累。释放的钙卫蛋白加剧了瘘管形成后的炎症、纤维化和内膜增生（IH）。我们将在三个特定目标和五个实验布局中测试我们的假设，以证明：1）钙卫蛋白对瘘管向内重塑的贡献; 2）CXCL 12和PU. 1增加钙卫蛋白和动静脉瘘失败风险的潜在机制; 3）PU. 1与人类队列中瘘管成熟结果之间的关系。我们将联合收割机精细显微外科技术和基因敲除小鼠相结合，成功实现我们的目标。我们还将询问100名随机选择的患者的人体生物储存库，这些患者正在进行两阶段的brachobasilic转位瘘的创建，以寻找静脉重塑和成熟不足后PU.1水平之间的关联。总之，随着这项提案的成功完成，我们正在为设计新药和细胞类型特异性干预措施铺平道路，以有效地针对动静脉瘘纤维化和IH并减少血管通路并发症。