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

基本信息

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
项目类别：
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

项目摘要

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 600,000 名美国人患有终末期肾病 (ESRD)，其中约 468,000 名透析患者依靠功能性血管通路来延长生命。成熟的动静脉 (A-V) 瘘因其较高的透析通路而成为首选。与合成移植物和中心静脉导管相比，通畅率更高，医疗成本更低。然而，约 40% 的新形成的瘘管无法成熟，也就是说，它们不能用于透析，因为狭窄使它们无法达到必要的血流。尽管 A-V 瘘术后狭窄对这些患者的发病率、死亡率和生活质量产生负面影响，但对其机制的研究很少。该转化建议建立了 CXCL12 和 PU.1/钙卫蛋白信号网络、内向重塑和瘘管结果之间的机制关系，以便设计靶向疗法来预防。我们的建议建立在强有力的科学前提之上，表明转录因子 PU.1 异位表达引起的 A-V 瘘术后钙卫蛋白积累与导致瘘管失败的内向重塑之间存在机制关系。细胞 (SMC) 衍生的钙卫蛋白会增加新形成的 A-V 瘘管狭窄和失败的风险。我们的机制假设是血液透析患者中 CXCL12 水平升高导致。血管系统中 PU.1 的异位表达以及 SMC 中钙卫蛋白的积累会导致后续瘘管形成后炎症、纤维化和内膜增生 (IH) 恶化。我们将在三个特定目标和五个实验布局中检验我们的假设。这将证明：1) 钙卫蛋白对瘘管内向重塑的贡献；2) CXCL12 和 PU.1 增加钙卫蛋白和A-V 瘘管失败的风险；3) PU.1 与人类队列中瘘管成熟结果之间的关系我们将改进显微外科技术并结合基因敲除小鼠来成功实现我们的目标。接受两阶段肱基底动脉转位瘘管创建的患者，以寻找静脉重塑后 PU.1 水平与成熟不足之间的关联。根据该提案，我们正在为新药和细胞类型特异性干预措施的设计铺平道路，以有效针对 A-V 瘘纤维化和 IH 并减少血管通路并发症。