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: 10001593
• 负责人: Alan Dardik
• 金额: $ 65.52万
• 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/10001593
• 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/antagonist; innovation; male; men; monolayer; mouse model; nanoparticle; nanoparticle delivery; novel; novel strategies; novel therapeutics; 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.

项目摘要 几种常见疗法的人类疾病的基石是将静脉用作管道 增加血流，例如动静脉瘘（AVF），这是血液透析的首选通道。然而， AVF的成熟和通畅不良，尤其是在妇女中，需要其他重新进行程序和 手术，反映了我们对导致成功的静脉重塑生物学的不完善的理解 静脉适应动脉环境。这种知识差距创造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沉积细胞外基质（ECM），使机械 抵抗血液透析程序的强度，每周用大孔针约束AVF壁。 转化生长因子（TGF）-β1调节许多细胞功能，包括ECM沉积和 重塑。我们提供令人兴奋的新数据：1）我们的创新鼠标AVF忠实地概括了 人类AVF成熟，包括〜1/3的失败率； 2）AVF的雌性小鼠的幅度减少了 与雄性小鼠相比，剪切应力； 3）我们可以在体内操纵TGF-β1功能，而TGF-β1需要 成功的早期AVF重塑； 4）在失败的小鼠AVF中，ECM增加，TGF-β1表达晚期 和smad2/tak1磷酸化； 5）在手术中，人AVF中的Smad2/tak1磷酸化增加 被删除以失败； 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，瘘管的手术创建可通过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TGF-β1晚期活性导致ECM沉积过多和新源性 增生导致AVF失败。降低晚期TGF-β1活性应减少ECM沉积和新内膜 增生，从而提高AVF通畅性。我们将使用我们的创新体内模型以及一本小说 生物反应器和分子工具，以以下特定目的检验我们的假设： 目的I：确定体内TGF-β信号传导的性别差异。 AIM II：确定最佳输送以减少晚期TGF-β1信号传导，从而增强静脉适应和 提高AVF通畅性。 AIM III：确定SMAD2或TAK1功能是否是TGFβ1介导的AVF重塑的机制。 通过确定过度TGF-β活性是否导致AVF，这项工作将产生持久的影响 失败，以及减少晚期TGF-β活性是否是增强AVF的临床翻译的宝贵策略 通畅。我们还将确定女性的AVF成熟减少是否由于静脉不足 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信号传导以改变血管壁的组成和强度，从而提高AVF通畅性。