CD39 in Vein Graft Arterialization

 描述(由申请人提供)：该提案描述了一项为期五年的培训计划，旨在发展心血管疾病的研究生涯，特别是血管领域的研究 生物学和炎症。候选人约根德拉·坎蒂博士是一名内科科学家，对静脉疾病非常感兴趣。主要导师(D.Pinsky，血管生物学)和一个由在血小板/血栓形成(M.Holinstat)、心血管流体/生物力学(D.Michele和S.Takayama)方面具有互补专业知识的非常成功的转化型科学家组成的咨询委员会已经组建，为候选人提供职业发展和研究方面的指导。研究环境在协作环境中提供广泛的资源、核心设施和内容专业知识。职业发展计划包括授课课程和研讨会。有一个身临其境的研究计划，旨在让候选人利用自己的实验室和R01资金，在实验研究设计、拨款撰写和过渡到独立研究员身份的知识方面发展初步数据和必要的技能。在动脉粥样硬化性血管疾病内科治疗失败的患者中，外科搭桥血管重建术最初可以恢复组织血流。 然而，最常用的自体人体静脉搭桥术的失败率比动脉搭桥术(每年10%-30%)高得不成比例，其特征是不良的重塑和狭窄。移植到动脉树中的静脉移植物暴露于搏动性扩张的动脉模式，这不是典型的静脉机械应力的特征，这会改变静脉移植物的表型。这一建议的压倒一切的假设是，通过脉动扩张的静脉移植物从“动脉化”的循环拉伸促进静脉内皮炎症，导致过度的血管重塑和梗阻性病变，除非被抑制血管炎症的内源性机制所抑制。一种潜在的这种机制是通过内皮CD39，一种酶，消散细胞外核苷酸“危险”信号(嘌呤)，这是炎症和血栓形成的有效激活剂。我们最近发现，CD39的表达是由层流流体切应力诱导的，是一种有效的动脉粥样硬化形成的抑制因子。然而，CD39的表达是否对另一个重要的生物力学刺激--静脉移植物中所见的内皮细胞的周期性拉伸--的反应尚未确定。我的初步数据支持最重要的假设，即CD39的表达是由周期性拉伸诱导的，如在静脉移植的“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细胞CD39对模拟静脉移植动脉化的不同程度的循环拉伸的反应；2)阐明循环拉伸诱导CD39表达的分子机制，重点是与CD39启动子相互作用的分子力学转导；以及3)确定血管CD39在减轻牵拉诱导的血管内皮功能障碍和加速的动脉化静脉移植模型中的作用。本研究的目的是明确CD39在抑制周期性牵张诱导的静脉内皮细胞应激中的作用，以加深我们对移植静脉扩张和重塑中的嘌呤能信号的理解。这项提议的潜在影响将是推进我们的方法，通过利用内源性保护机制来改善静脉移植物的通畅性，并促进奉献精神的内科医生-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.