Enhancing venous adaptation to the arterial environment

增强静脉对动脉环境的适应

• 批准号: 9102364
• 负责人: Alan Dardik
• 金额: $ 47.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9102364
• 关键词: Address; Adult; Arteries; Arteriovenous fistula; Biology; Bioreactors; Blood Circulation; Blood Vessels; Caliber; Characteristics; Clinical; Critical Pathways; Data; Development; Embryo; End stage renal failure; Endothelial Cells; Endothelium; Environment; Eph Family Receptors; Ephrin-B2; Ephrins; Exhibits; Expenditure; Failure; Goals; Healthcare; Hemodialysis; Human; In Vitro; Knockout Mice; Knowledge; Lead; Length; Ligands; Mediating; Medical; Modeling; Mus; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Phosphorylation; Procedures; Rattus; Resistance; Resources; Signal Transduction; Surgeon; Testing; Therapeutic Intervention; Tyrosine; Vein graft; Veins; Venous; Work; clinically relevant; hemodynamics; human disease; improved; in vitro Model; in vivo; in vivo Model; innovation; member; monolayer; mouse model; mutant; novel; novel strategies; oxidative damage; prevent; public health relevance; receptor; response; shear stress; vascular inflammation

 DESCRIPTION (provided by applicant): A cornerstone of several common therapies for human diseases is the surgical use of a vein as an arterial conduit. Surgeons frequently create arteriovenous fistulae (AVF), the preferred access for hemodialysis. However, the poor maturation and patency of AVF, 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 medical need for novel approaches to enhance venous adaptation and maturation, to increase successful use of venous conduits. The tyrosine kinase receptor Eph-B4 is an embryonic determinant of veins. Diminished Eph-B4 expression is associated with shear stress conditions with laminar-like flow such as occurs during vein graft adaptation in humans and mice. We present exciting new data that: 1) our innovative mouse model of AVF faithfully recapitulates human AVF maturation including the presence of disturbed shear stress and an approximately 1/3 failure rate; 2) in both humans and mice, Eph-B4 expression initially increases during AVF adaptation to the arterial environment; 3) Eph-B4 function is essential for AVF remodeling; 4) Eph-B4 tyrosine- 774 is a critical regulator of Eph-B4 phosphorylation and activation of downstream signaling in vitro; 5) manipulation of Eph-B4 function via delivery of wild type or mutant Eph-B4 in vivo alters AVF remodeling; and 6) Akt-1 knockout mice have reduced AVF remodeling and altered responses to Eph-B4 stimulation. Our data suggests that surgical placement of a vein into the arterial environment regulates Eph-B4 phosphorylation and/or expression that is critical for successful venous adaptation and AVF maturation. We hypothesize that altering Eph-B4 activity will improve venous adaptation to the arterial circulation, thereby improving AVF maturation. We will use our innovative in vivo model of AVF maturation, as well as use a bioreactor that can control and deliver hemodynamic loads to small diameter vessels and endothelial monolayers in vitro, to test our hypothesis with the following specific aims: Aim I: Determine optimal Eph-B4 manipulation and delivery to enhance venous adaptation to the arterial environment and improve AVF maturation. Aim II: Determine whether Akt function is a mechanism of Eph-B4-mediated AVF maturation. The work in this proposal will have lasting impact by establishing that Eph-B4 is a component of the mechanotransduction mechanism in veins. We will test our novel hypothesis that Eph-B4 activity, or lack thereof, defines venous phenotype and function. We use an innovative strategy, as well as innovative in vivo and in vitro models, to manipulate Eph-B4 signaling and optimize delivery in vivo to alter vessel identity and thereby improve AVF maturation.

 描述（通过应用程序提供）：几种常见人类疾病疗法的基石是将静脉作为人工制品导管的手术用途。外科医生经常会产生动静脉瘘（AVF），这是血液透析的首选访问。但是，需要额外的重新进行手术和手术的AVF的成熟和通畅性不佳，这反映了我们对静脉重塑的生物学的不完善，从而导致成功地适应了对人工制品环境的静脉调整。这种知识差距创造了对新方法的未满足的医学需求，以增强静脉适应和成熟，以增加静脉导管的成功使用。酪氨酸激酶受体EPH-B4是静脉的胚胎确定。 EPH-B4表达的降低与层状流动的剪切应力条件有关，例如在人类和小鼠的静脉移植物适应过程中发生。我们提供了令人兴奋的新数据：1）我们的AVF创新小鼠模型忠实地概括了人类AVF的成熟，包括存在受影响的剪切应力和大约1/3的失败率； 2）在人类和小鼠中，EPH-B4表达最初在AVF适应伪像的过程中增加。 3）EPH-B4功能对于AVF重塑至关重要； 4）EPH-B4酪氨酸-774是EPH-B4磷酸化的关键调节剂和体外下游信号传导的激活； 5）通过在体内递送野生型或突变体Eph-B4来操纵EPH-B4功能；和6）AKT-1敲除小鼠减少了AVF重塑和对EPH-B4刺激的反应。我们的数据表明，将静脉放置在ART环境中的外科手术调节EPH-B4磷酸化和/或表达对于成功的静脉适应和AVF成熟至关重要。我们假设改变EPH-B4活性将改善对动脉循环的静脉适应，从而改善AVF的成熟。我们将使用我们的创新体内AVF成熟模型，并使用可以在体外控制和输送血液动力学负荷的生物反应器，并在体外进行小直径vissels和内皮单层，用以下特定目的来测试我们的假设：AIM I：确定最佳的EPH-B4操纵和递送以增强AAV型适应性，并改善了AAV的av anter anteratial anteratial antertration。 AIM II：确定AKT函数是否是EPH-B4介导的AVF成熟的机制。该提案中的工作将通过确定EPH-B4是静脉转导机制的组成部分，从而产生持久的影响。我们将测试我们的新假设，即EPH-B4活性或缺乏其定义静脉表型和功能。我们使用创新的策略以及体内和体外模型的创新策略来操纵EPH-B4信号传导并优化体内的输送以改变血管身份，从而改善AVF成熟。