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: 10580859
• 负责人: Luis Gonzalez
• 金额: $ 1.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10580859
• 关键词: Adult; Affect; Arteriovenous fistula; Blood Vessels; Catheters; Cell Proliferation; Cell physiology; Cells; Collagen; Collagen Type I; Data; Deposition; End stage renal failure; Ensure; Environment; Extracellular Matrix; Failure; Feedback; Female; Fistula; Genetic Transcription; Goals; Growth Factor; Health Care Costs; Hemodialysis; Histologic; Homeostasis; Hyperplasia; Immune response; Infection; Information Systems; Intervention; Kidney; Kidney Transplantation; Knockout Mice; Knowledge; Legal patent; Link; Mechanical Stress; Mechanics; Medial; Medical; Mentors; Modeling; Molecular; Morbidity - disease rate; Mus; Needles; Nonstructural Protein; Outcome; Patients; Persons; Physicians; Procedures; Proteins; Public Health; Puncture procedure; Quality of life; Regulation; Renal Replacement Therapy; Reporting; Research Personnel; Resources; Role; Safe Sex; Scientist; Sex Differences; Signal Transduction; Structure; Surgeon; Survival Rate; Tenascin; Testing; Thick; Tissues; United States; Universities; Veins; Venous; Woman; Work; arteriovenous graft; cell motility; cytokine; differential expression; hemodynamics; immunoregulation; improved; in vivo; male; mechanical properties; men; mortality; mouse model; novel strategies; novel therapeutic intervention; protein expression; response; sex; tool; ultrasound

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.

项目摘要/摘要 末期肾脏疾病（ESRD）是一个严重的公共卫生问题，全球死亡率提高。这 美国肾脏数据系统报告说，2017年美国有超过740,000人受到影响。 但是，所有ESRD患者中只有约30％接受肾脏移植，这是最理想的选择，离开 大多数患者接受血液透析治疗。不幸的是，AVF是最糟糕的程序 血管外科医生执行的所有程序之间的通知。 AVF无法成熟，它是扩张和增稠的， 在约20-50％的病例中，导致“早期失败”需要重新介入以促进成功的成熟。在 由于新蛋白质增生而导致的第一年，“晚期失败”的AVF发生在〜35-40％ （NIH）导致壁增厚过多，导致AVF阻塞导致患者痛苦，发病率 和死亡率。与男性相比，女性的AVF成熟率更低，导致AVF降低 利用率。该项目提出的建议使用我们既定的主动脉鼠鼠标模型来研究女性为什么 具有较差的AVF结局，并研究静脉重塑期间Tenascin-C（TNC）的作用；我们的 初步数据显示，成年小鼠静脉中不存在TNC的表达，但在静脉壁中表达 AVF创建。该提案的总体目标是调查操纵TNC功能是否可以 充当提高AVF通畅性的新理论策略。该项目的第一个目的决定了 野生型和TNC-的细胞功能和/或性别之间的AVF成熟和通畅性差异差异 KO老鼠。我们的初步数据表明，小鼠中的AVF产生会导致血液动力学差异 性别以及蛋白质的差异表达，其中一些直接受TNC的影响。第二个 AIM确定野生型和TNC-KO小鼠的性别之间IVC机械性能的差异 基线和AVF创建之后，并评估TNC在细胞外基质（ECM）组成中的作用。我会 还可以确定TGF-B1信号传导的操纵如何影响TNC诱导的NIH，因为TGF-B1（谁） 持续的表达导致NIH，诱导TNC表达，从而产生正反馈回路，从而导致 TGF-B1和TNC的水平增加。因此，该项目将确定TNC在静脉中的作用 AVF创建后进行重塑，并确定对性别差异的性别之间的关键差异 AVF结果。完成该项目的目标将显示提高AVF通畅率的新策略 这降低了并发症和医疗保健成本以及患者的改善生活质量 ESRD。