Regulation of venous remodeling and arteriovenous fistula patency by the matricellular protein Tenascin-C

项目摘要/摘要 终末期肾病(ESRD)是一个严重的公共卫生问题，全球死亡率不断上升； 美国肾脏数据系统报告称，2017年美国有超过74万人受到影响。 然而，只有30%的终末期肾病患者接受了肾脏移植，这是最可取的选择，离开 大多数患者需要进行血液透析治疗。不幸的是，AVF是最糟糕的手术 血管外科医生进行的所有手术中的通畅性。AVF不成熟，即扩张增厚， 在约20-50%的情况下，导致“早期失败”，需要重新干预以促进成功成熟。在……里面 成熟的动静脉瘘在第一年内因新生内膜增生而发生约35-40%的“晚期衰竭”。 (NIH)会导致室壁过度增厚，导致AVF闭塞，导致患者痛苦、发病率 和死亡率。与男性相比，女性的AVF成熟率更低，导致AVF减少。 利用率。该项目建议使用我们已建立的腹主动脉腔小鼠模型来研究为什么女性 有较差的AVF预后，并探讨TnC(TNC)在静脉重构中的作用； 初步数据显示，TNC在成年小鼠静脉中不表达，但在成年小鼠静脉壁中表达 AVF创建。这项提议首要目标是调查TNC功能的操纵是否可以 作为一种新的治疗策略来改善动静脉瘘的通畅性。这个项目的第一个目标是确定 野生型和TNC的细胞功能和/或AVF成熟和开放程度性别之间的差异 Ko老鼠。我们的初步数据显示，在小鼠中，AVF的产生导致了 性别，以及蛋白质的差异表达，其中一些直接受到TNC的影响。第二 目的测定野生型和TNC-KO小鼠下腔静脉力学性能的性别差异。 基线和AVF创建后，评估TNC在细胞外基质(ECM)组成中的作用。这就做 还确定了对转化生长因子-β1信号的操纵如何影响TNC诱导的NIH，因为转化生长因子-β1，其 持续表达导致NIH，诱导TNC表达，从而产生正反馈循环，从而导致 转化生长因子-β1和肿瘤坏死因子水平均升高。因此，本项目将确定TNC在静脉中的作用 动静脉瘘形成后的重塑和确定性别之间的关键差异 AVF结果。实现该项目的目标将展示提高AVF通畅率的新策略 减少并发症和医疗成本，并提高患者的生活质量 ESRD。

PROJECT SUMMARY/ABSTRACT End-stage renal disease (ESRD) is a serious public health issue with increasing mortality worldwide; the United States Renal Data System reported that over 740,000 people were affected in the U.S. in 2017. However, only ~30% of all patients with ESRD receive kidney transplants, the most desirable option, leaving the majority of patients to be treated with hemodialysis. Unfortunately, AVF is the procedure with the worst patency among all procedures performed by vascular surgeons. AVF fail to mature, that is dilate and thicken, in ~20-50% of cases, resulting in “early failure” requiring reinterventions to promote successful maturation. In the AVF that do mature, “late failure” occurs in ~35-40% during the first year due to neointimal hyperplasia (NIH) that leads to excessive wall thickening, resulting in AVF occlusion leading to patient suffering, morbidity and mortality. Women have even worse rates of AVF maturation compared to men, resulting in reduced AVF utilization. This project proposes to use our established aortocaval mouse model to investigate why women have worse AVF outcomes and to investigate the role of tenascin-C (TnC) during venous remodeling; our preliminary data show TnC expression is absent in adult mouse veins but is expressed in the vein wall after AVF creation. The overarching goal of this proposal is to investigate whether manipulation of TnC function may serve as a novel therapeutic strategy to improve AVF patency. The first Aim of this project determines differences in cell function and/or reduced AVF maturation and patency between sexes in wild-type and TnC- KO mice. Our preliminary data shows that AVF creation in mice results in hemodynamic differences between sexes, as well as differential expression of proteins, some of which are directly influenced by TnC. The second Aim determines differences in IVC mechanical properties between sexes in wild-type and TnC-KO mice at baseline and after AVF creation, and assesses the role of TnC in extracellular matrix (ECM) composition. I will also determine how manipulation of TGF-b1 signaling influences TnC-induced NIH, since TGF-b1, whose sustained expression leads to NIH, induces TnC expression that creates a positive feedback loop resulting in increased levels of both TGF-b1 and TnC. Therefore, this project will determine the role of TnC in venous remodeling after AVF creation and identify critical differences between sexes responsible for differences in AVF outcomes. Accomplishing the aims of this project will show new strategies to improve AVF patency rates that reduce complications and healthcare costs as well as improve quality of life for patients suffering from ESRD.