Manipulating the matrix to improve arteriovenous fistula patency

操纵基质以改善动静脉内瘘的通畅

• 批准号: 10460349
• 负责人: Alan Dardik
• 金额: $ 65.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460349
• 关键词: Address; Arteriovenous fistula; Biology; Bioreactors; Blood Vessels; Blood flow; Caliber; Cell Proliferation; Cell physiology; Cells; Clinical; Data; Deposition; Encapsulated; End stage renal failure; Endothelium; Environment; Expenditure; Extracellular Matrix; Failure; Female; Fistula; Healthcare; Hemodialysis; Human; Hyperplasia; In Vitro; Intervention; Knowledge; Lead; Mechanics; Mediating; Methods; Modeling; Molecular; Mus; Needles; Operative Surgical Procedures; Patients; Phosphorylation; Procedures; Puncture procedure; Resources; Sex Differences; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; System; Testing; Time; Transforming Growth Factors; Veins; Venous; Woman; Work; base; clinical translation; hemodynamics; human disease; human female; human male; improved; in vivo; in vivo Model; inhibitor; innovation; male; men; monolayer; mouse model; nanoparticle; nanoparticle delivery; novel; novel strategies; novel therapeutic intervention; response; shear stress; tool

Project Summary A cornerstone of several common therapies for human diseases is the use of a vein as a conduit to increase blood flow such as the arteriovenous fistula (AVF), the preferred access for hemodialysis. However, the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful venous adaptation to the arterial environment. This knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby to increase successful clinical use of venous conduits. Successful venous remodeling requires deposition of extracellular matrix (ECM), enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. Transforming growth factor (TGF)-β1 regulates numerous cellular functions, including ECM deposition and remodeling. We present exciting new data that: 1) our innovative mouse model of AVF faithfully recapitulates human AVF maturation including an ~1/3 failure rate; 2) female mice with AVF have diminished magnitudes of shear stress compared to male mice; 3) we can manipulate TGF-β1 function in vivo and TGF-β1 is required for successful early AVF remodeling; 4) in failed mouse AVF there is increased ECM, late TGF-β1 expression and smad2/tak1 phosphorylation; 5) there is increased smad2/tak1 phosphorylation in human AVF surgically removed for failure; 6) we developed an innovative nanoparticle tool to manipulate TGF-β1 signaling in vivo. Our data suggest that surgical creation of a fistula stimulates early TGF-β1 activation via smad2/3 and/or tak1 phosphorylation that is critical for successful early venous adaptation and AVF maturation. We hypothesize that exuberant late TGF-β1 activity results in excessive ECM deposition and neointimal hyperplasia causing AVF failure. Reducing late TGF-β1 activity should reduce ECM deposition and neointimal hyperplasia, thereby improving AVF patency. We will use our innovative in vivo model, as well as a novel bioreactor and molecular tools, to test our hypothesis with the following specific aims: Aim I: Determine whether there are sex differences in TGF-β signaling in vitro and AVF remodeling in vivo. Aim II: Determine optimal delivery to reduce late TGF-β1 signaling thereby enhancing venous adaptation and improving AVF patency. Aim III: Determine whether smad2 or tak1 function is a mechanism of TGFβ1-mediated AVF remodeling. This work will have lasting impact by establishing whether excessive TGF-β activity leads to AVF failure, and whether reducing late TGF-β activity is a valuable strategy for clinical translation to enhance AVF patency. We will also determine whether the reduced AVF maturation in women is due to insufficient venous remodeling or increased neointimal hyperplasia. We use an innovative strategy and novel tools to manipulate TGF-β signaling to alter vessel wall composition and strength and thereby improve AVF patency.

项目概要 人类疾病的几种常见疗法的基石是使用静脉作为导管 增加血流量，例如动静脉内瘘（AVF），是血液透析的首选途径。然而， AVF 的成熟度和通畅性较差，尤其是女性，需要额外的重做手术和 手术反映了我们对导致成功的静脉重塑生物学的不完全理解 静脉对动脉环境的适应。这种知识差距造成了对小说的未满足的需求 增强静脉重塑的方法，从而增加静脉导管的成功临床使用。 成功的静脉重塑需要细胞外基质 (ECM) 的沉积，从而实现机械 抵抗每周 3 次用大口径针穿刺 AVF 壁的血液透析程序的强度。 转化生长因子 (TGF)-β1 调节多种细胞功能，包括 ECM 沉积和 重塑。我们提供了令人兴奋的新数据：1）我们的创新小鼠 AVF 模型忠实地再现了 人类 AVF 成熟，失败率约为 1/3； 2) 患有 AVF 的雌性小鼠的 与雄性小鼠相比的剪切应力； 3）我们可以在体内操纵TGF-β1的功能，并且TGF-β1是 成功的早期 AVF 重塑； 4) 失败的小鼠 AVF 中 ECM 增加，晚期 TGF-β1 表达增加 和 smad2/tak1 磷酸化； 5) 手术后人 AVF 中 smad2/tak1 磷酸化增加 因失败而被删除； 6) 我们开发了一种创新的纳米颗粒工具来操纵体内 TGF-β1 信号传导。 我们的数据表明，手术创建瘘管可通过 smad2/3 刺激早期 TGF-β1 激活 和/或 tak1 磷酸化对于成功的早期静脉适应和 AVF 成熟至关重要。我们 假设旺盛的晚期 TGF-β1 活性导致过度的 ECM 沉积和新生内膜 增生导致 AVF 失败。减少晚期 TGF-β1 活性应减少 ECM 沉积和新生内膜 增生，从而改善 AVF 通畅性。我们将使用我们创新的体内模型以及新颖的 生物反应器和分子工具，以测试我们的假设，其具体目标如下： 目标 I：确定体外 TGF-β 信号传导和体内 AVF 重塑是否存在性别差异。 目标 II：确定最佳输送方式以减少晚期 TGF-β1 信号传导，从而增强静脉适应和 改善 AVF 的通畅性。 目标 III：确定 smad2 或 tak1 功能是否是 TGFβ1 介导的 AVF 重塑的机制。 这项工作将通过确定过度的 TGF-β 活性是否会导致 AVF 产生持久影响 失败，以及降低晚期 TGF-β 活性是否是临床转化以增强 AVF 的一个有价值的策略 通畅。我们还将确定女性 AVF 成熟度降低是否是由于静脉血不足所致 重塑或增加新内膜增生。我们使用创新的策略和新颖的工具来操纵 TGF-β 信号传导可改变血管壁成分和强度，从而改善 AVF 通畅性。