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
• 负责人: Luis Gonzalez
• 金额: $ 3.16万
• 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 2024-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540301
• 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; Gold; Growth Factor; Health Care Costs; Hemodialysis; Histologic; Homeostasis; Hyperplasia; Immune response; Infection; Information Systems; Kidney; Kidney Transplantation; Knockout Mice; Knowledge; 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; Time; Tissues; United States; Universities; Veins; Venous; Woman; Work; arteriovenous graft; cell motility; cytokine; differential expression; hemodynamics; 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.

项目总结/摘要 终末期肾病（ESRD）是一个严重的公共卫生问题，在全球范围内死亡率不断上升; 美国肾脏数据系统报告说，2017年美国有超过74万人受到影响。 然而，只有约30%的终末期肾病患者接受肾移植，这是最理想的选择， 大多数患者接受血液透析治疗。不幸的是，AVF是最糟糕的手术 血管外科医生进行的所有手术中的通畅率。AVF未发育成熟，即扩张和扩张， 在约20-50%的病例中，导致“早期失败”，需要再次干预以促进成功成熟。在 由于新生内膜增生，在第一年内，约35-40%的AVF成熟，“晚期衰竭”发生 (NIH)导致壁过度增厚，导致AVF闭塞，导致患者痛苦、发病 and mortality.与男性相比，女性AVF成熟率更低，导致AVF减少 利用率这个项目建议使用我们建立的下腔静脉小鼠模型来研究为什么女性 AVF结局更差，并研究腱生蛋白C（TnC）在静脉重塑中的作用;我们 初步数据显示TnC在成年小鼠静脉中不表达，但在注射后在静脉壁中表达。 AVF创建。这项提案的首要目标是研究是否可以操纵TnC功能， 作为改善AVF通畅性的新治疗策略。该项目的第一个目标是确定 在野生型和TnC中，性别之间的细胞功能差异和/或AVF成熟和通畅性降低， KO小鼠。我们的初步数据表明，在小鼠中建立AVF会导致 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 目的是确定野生型和TnC-KO小鼠在不同性别之间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 还确定了如何操纵TGF-β 1信号转导影响TnC诱导的NIH，因为TGF-β 1，其 持续表达导致NIH，诱导TnC表达，产生正反馈回路， TGF-β 1和TnC水平升高。因此，本项目将确定TnC在静脉 AVF创建后的重塑，并确定性别之间的关键差异， AVF结局。实现本项目的目标将显示提高AVF通畅率的新策略 减少并发症和医疗保健成本，并改善患者的生活质量， 终末期肾病