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

基质细胞蛋白 Tenascin-C 对静脉重塑和动静脉瘘通畅的调节

基本信息

  • 批准号:
    10580859
  • 负责人:
  • 金额:
    $ 1.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-16 至 2023-10-15
  • 项目状态:
    已结题

项目摘要

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.
项目概要/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;这 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,只有约 30% 的 ESRD 患者接受肾移植(这是最理想的选择),这使得 大部分患者需接受血液透析治疗。不幸的是,AVF 是最糟糕的手术 血管外科医生执行的所有手术的通畅性。 AVF未成熟,即扩张、增厚, 约 20-50% 的病例会导致“早期失败”,需要重新干预以促进成功成熟。在 成熟的 AVF 中,由于新内膜增生,第一年约有 35-40% 发生“晚期失败” (NIH) 导致室壁过度增厚,导致 AVF 闭塞,导致患者痛苦和发病 和死亡率。与男性相比,女性 AVF 成熟率更差,导致 AVF 减少 利用率。该项目建议使用我们建立的主动脉腔静脉小鼠模型来研究为什么女性 AVF 结果较差,并研究生腱蛋白-C (TnC) 在静脉重塑过程中的作用;我们的 初步数据显示,成年小鼠静脉中不存在 TnC 表达,但在成年小鼠静脉壁中表达 AVF 创建。该提案的首要目标是研究 TnC 功能的操纵是否可以 作为改善 AVF 通畅的新型治疗策略。该项目的第一个目标确定 野生型和 TnC- 性别之间的细胞功能差异和/或 AVF 成熟度和通畅性降低 KO老鼠。我们的初步数据表明,小鼠 AVF 的产生导致小鼠之间的血流动力学差异 性别以及蛋白质的差异表达,其中一些直接受 TnC 影响。第二个 目标确定野生型和 TnC-KO 小鼠性别间 IVC 机械特性的差异 基线和 AVF 创建后,并评估 TnC 在细胞外基质 (ECM) 组成中的作用。我会 还确定了 TGF-b1 信号传导如何影响 TnC 诱导的 NIH,因为 TGF-b1 的 持续表达导致 NIH,诱导 TnC 表达,从而创建正反馈循环,从而导致 TGF-b1 和 TnC 水平升高。因此,该项目将确定 TnC 在静脉中的作用 AVF 创建后的重塑并确定性别之间导致差异的关键差异 AVF 结果。实现该项目的目标将展示提高 AVF 通畅率的新策略 减少并发症和医疗费用,并提高患有以下疾病的患者的生活质量 终末期肾病。

项目成果

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Luis Gonzalez其他文献

Luis Gonzalez的其他文献

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{{ truncateString('Luis Gonzalez', 18)}}的其他基金

Regulation of venous remodeling and arteriovenous fistula patency by the matricellular protein Tenascin-C
基质细胞蛋白 Tenascin-C 对静脉重塑和动静脉瘘通畅的调节
  • 批准号:
    10540301
  • 财政年份:
    2021
  • 资助金额:
    $ 1.7万
  • 项目类别:

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