Enhancing venous adaptation to the arterial environment

增强静脉对动脉环境的适应

• 批准号: 9460535
• 负责人: Alan Dardik
• 金额: $ 46.44万
• 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/9460535
• 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; mechanotransduction; 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（由申请人提供）：人类疾病的几种常见疗法的基石是外科手术使用静脉作为动脉导管。外科医生经常制造动静脉瘘（AVF），这是血液透析的首选途径。然而，AVF 的成熟度和通畅性较差，需要额外的重做程序和手术，反映出我们对导致静脉成功适应动脉环境的静脉重塑生物学的理解不完善。这种知识差距造成了对增强静脉适应和成熟的新方法的未满足的医疗需求，以增加静脉导管的成功使用。 酪氨酸激酶受体 Eph-B4 是静脉的胚胎决定因子。 Eph-B4 表达减少与层流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适应过程中发生的情况。我们提供了令人兴奋的新数据：1）我们创新的 AVF 小鼠模型忠实地再现了人类 AVF 的成熟过程，包括存在剪切应力干扰和大约 1/3 的失败率； 2) 在人类和小鼠中，Eph-B4 表达最初在 AVF 适应动脉环境期间增加； 3）Eph-B4功能对于AVF重塑至关重要； 4) Eph-B4酪氨酸-774是体外Eph-B4磷酸化和下游信号激活的关键调节因子； 5) 通过在体内递送野生型或突变型 Eph-B4 来操纵 Eph-B4 功能，改变 AVF 重塑； 6) Akt-1 基因敲除小鼠的 AVF 重塑减少并改变了对 Eph-B4 刺激的反应。 我们的数据表明，手术将静脉置入动脉环境可调节 Eph-B4 磷酸化和/或表达，这对于静脉适应和 AVF 成熟的成功至关重要。我们假设改变 Eph-B4 活性将改善静脉对动脉循环的适应，从而改善 AVF 的成熟。我们将使用我们创新的 AVF 成熟体内模型，以及使用可以在体外控制和向小直径血管和内皮单层输送血流动力学负荷的生物反应器，以测试我们的假设，其具体目标如下： 目标 I：确定最佳的 Eph-B4 操作和输送，以增强静脉对动脉环境的适应并改善 AVF 成熟。 目标 II：确定 Akt 功能是否是 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 是静脉机械传导机制的组成部分而产生持久影响。我们将测试我们的新假设，即 Eph-B4 活性或缺乏活性决定静脉表型和功能。我们使用创新策略以及创新的体内和体外模型来操纵 Eph-B4 信号传导并优化体内递送，以改变血管身份，从而改善 AVF 成熟。