CD39 in Vein Graft Arterialization

 描述（由申请人提供）：该提案描述了一个为期五年的培训计划，用于发展心血管疾病的研究事业，特别是在血管 生物学和炎症。候选人Yogendra Kanthi博士是一位对静脉疾病感兴趣的医生兼科学家。第一个导师（D。平斯基，血管生物学）和一个非常成功的咨询委员会，翻译科学家与血小板/血栓形成的补充专业知识（M。Holinstat）、心血管流体/生物力学（D. Michele和S.为候选人提供职业发展和调查方面的指导。研究环境提供了广泛的资源，核心设施和内容专业知识在协作环境。职业发展计划包括教学课程和研讨会。有一个沉浸式的研究计划，旨在为候选人开发初步数据和必要的技能，在实验研究设计，赠款写作和知识过渡到独立的研究者地位，与他自己的实验室和R 01资金。在动脉粥样硬化血管疾病的药物治疗失败的患者中，通过外科旁路移植物进行的血运重建最初恢复了组织血流。 然而，最常用的自体人静脉旁路移植物比动脉旁路移植物具有不成比例的更高的失败率（每年10-30%），其特征在于不良重塑和狭窄。移植到动脉树中的静脉移植物暴露于动脉搏动扩张模式，而不是典型的静脉机械应力的特征，这改变了静脉移植物的表型。这一建议的主要假设是，由“动脉化”引起的脉动扩张引起的静脉移植物的周期性拉伸促进静脉内皮炎症，导致过度的血管重塑和阻塞性病变，除非受到抑制血管炎症的内源性机制的抑制。一种潜在的这种机制是通过内皮CD 39，一种消散细胞外核苷酸“危险”信号（嘌呤）的酶，其是炎症和血栓形成的有效激活剂。我们最近发现，CD 39的表达是诱导层流流体剪切应力，是一个有效的抑制动脉粥样硬化。然而，CD 39表达是否对另一个重要的生物力学刺激-血管移植物中所见的内皮细胞周期性拉伸-有反应尚不清楚。我的初步数据支持了CD 39表达是由周期性牵张诱导的这一重要假设，正如在静脉移植物动脉化中所见。“该提案的具体目的是：1）确定动脉和静脉内皮CD 39对不同程度的循环拉伸模拟静脉移植物动脉化的反应; 2）阐明循环拉伸诱导CD 39表达的分子机制，重点是与CD 39启动子相互作用的分子机械转换器;和3）在鼠动脉化静脉移植物模型中确定血管CD 39在减轻牵张诱导的内皮功能障碍和加速的内膜增生中的影响。本提案的目的是确定CD 39在抑制周期性牵张诱导的静脉内皮应力中的作用，以增强我们对静脉移植物扩张和重塑中嘌呤能信号传导的理解。该提案的潜在影响将是通过利用内源性保护机制来推进我们改善静脉移植物通畅性的方法，并提高敬业的医生-科学家的职业发展。

 DESCRIPTION (provided by applicant): The proposal describes a five-year training program for development of a research career in cardiovascular disease, particular in the field of vascular biology and inflammation. The candidate, Dr. Yogendra Kanthi, is a physician-scientist with focused interest in venous disease. The primary mentor (D. Pinsky, vascular biology) and an advisory committee of highly successful, translational scientists with complementary expertise in platelets/thrombosis (M. Holinstat), cardiovascular fluids/biomechanics (D. Michele and S. Takayama) have been assembled to provide the candidate with guidance in career development and investigation. The research environment provides extensive resources, core facilities, and content expertise in a collaborative setting. The career development plan includes didactic courses and seminars. There is an immersive research program designed for the candidate to develop both preliminary data and the requisite skillset in experimental study design, grant writing, and knowledge to transition to independent investigator status, with his own laboratory and R01 funding. In patients who fail medical management of atherosclerotic vascular disease, revascularization by surgical bypass grafts initially restores tissue blood flow. However, the most commonly used autologous human vein bypass grafts carry a disproportionately higher rate of failure than arterial bypass grafts (10-30% per year), characterized by adverse remodeling and stenosis. Vein grafts transplanted into an arterial tree are exposed to arterial patterns of pulsatile distention uncharacteristic of typical venous mechanical stresses which alter vein graft phenotype. The overriding hypothesis of this proposal is that cyclic stretching of vein grafts by pulsatile distension from "arterialization" promotes venous endothelial inflammation leading to excessive vascular remodeling and obstructive lesions, unless curbed by endogenous mechanisms that suppress vascular inflammation. One potential such mechanism is through endothelial CD39, an enzyme that dissipates extracellular nucleotide "danger" signals (purines) which are potent activators of inflammation and thrombosis. We recently discovered that CD39 expression is induced by laminar fluid shear stresses and is a potent suppressor of atherogenesis. However, whether CD39 expression responds to another significant biomechanical stimulus- cyclic stretching of the endothelium as seen in vein grafts- is not yet defined. My preliminary data supports the overriding hypothesis that CD39 expression is induced by cyclic stretch as seen in vein graft "arterialization." The Specific Aims of the proposal are to: 1) Define the response of arterial and venous endothelial CD39 to varying degrees of cyclic stretch simulating arterialization of vein grafts; 2) Elucidate the molecular mechanisms by which CD39 expression is induced by cyclic stretch with a focus on molecular mechanotransducers interacting with the CD39 promoter; and 3) Define the impact of vascular CD39 in mitigating stretch-induced endothelial dysfunction and accelerated intimal hyperplasia in a murine arterialized vein graft model. The goal of this proposal is to define the role of CD39 in suppressing cyclic stretch-induced venous endothelial stress to enhance our understanding of purinergic signaling in vein graft distention and remodeling. The potential impact of this proposal will be to advance our approaches to improve vein graft patency by leveraging endogenous protective mechanisms and to enhance the career development of a dedication physician-scientist.