CAREER: Modulating endothelial cell function using targeted electrical stimulation

在癌症和其他一些非恶性疾病中，排列在血管上的内皮细胞会变得功能失调，干扰药物输送，引起炎症并阻碍愈合。然而，在不向整个循环中注入药物的情况下调节体内特定部位的内皮细胞功能是一个主要挑战。这个教师早期职业发展计划（Career）提案的目标是通过开发一种技术来解决这个重要的问题，这种技术可以使用脉冲电场来靶向刺激内皮细胞，这种脉冲电场可以通过医疗设备传递到身体的所需区域。该项目将研究脉冲电场波形，使内皮细胞屏障功能的控制和特异性改变成为可能，确定介导这种反应的生物学途径，并测试这种方法是否能增强对肿瘤的药物输送。从该提案中获得的新工具和知识可以对内皮细胞在各种疾病中的作用进行新的研究，并改善数百万癌症患者的治疗结果。本提案中的协同教育和外联活动将开展基于项目的活动，以提高本科生和高中生对用电作为一种治疗形式的医疗设备的认识，并为他们进入劳动力市场或接受医疗设备主题的高等教育做好准备。血管内皮细胞（ECs）在电刺激神经和骨骼肌时调节离子的通过，传递生物电信号，并表现出屏障通透性的改变。尽管有如此多样的生物电反应，但ec通常不被认为是电可兴奋的。本研究的目的是探讨脉冲电场（PEFs）是否可以被设计成选择性地刺激内皮细胞以改变血管通透性，并阐明介导这种反应的信号通路。潜在的假设是，PEF将触发ECs中的肌动蛋白应激纤维重塑，从而通过沿血管内皮生长因子受体(VEGFR) -粘附体连接轴信号传导的连接蛋白易位增加毛细血管屏障的通透性。在Aim 1中，将量化经PEF处理的EC单层中屏障功能改变的动力学。在Aim 2中，将评估VEGFR - cadherin信号在改变屏障通透性中的作用，并研究潜在的血管生成反应。在Aim 3中，PEF参数将被设计用于选择性刺激ECs，然后测试是否能增加化疗对肿瘤的递送。定义介导EC对PEF反应的信号机制的新工具和机制研究可以开辟几条新的多学科研究路线，并使药物递送取得重大进展。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Endothelial cells that line blood vessels become dysfunctional in cancer and several other non-malignant disease conditions, interfering with drug delivery, causing inflammation and impeding healing. However, modulating endothelial cell function at specific locations within the body without infusing drugs into the entire circulation is a major challenge. The objective of this Faculty Early Career Development Program (CAREER) proposal is to tackle this important question by developing a technology for the targeted stimulation of enendothelial cells using pulsed electric fields that can be delivered to the desired region of the body using medical devices. The project will study pulsed electric field waveforms that enable controlled and specific alteration of the endothelial cell barrier function, identify the biological pathways that mediate this response, and test this approach for enhancing drug delivery to tumors. The novel tools and knowledge gained from this proposal can enable new investigations on the role of endothelial cells in various diseases and improve treatment outcomes for millions of cancer patients. Synergistic educational and outreach activities in this proposal will develop project-based activities to create awareness in undergraduate and high school students about medical devices that use electricity as a form of therapy and to prepare them to enter the workforce or pursue higher education on the topic of medical devices. The endothelial cells (ECs) lining blood vessels regulate the passage of ions, transmit bioelectric signals, and manifest altered barrier permeability during electrical stimulation of nerves and skeletal muscles. Despite such diverse bioelectric responses, ECs have not been conventionally considered to be electrical excitable. The research objective of this proposal is to investigate whether pulsed electric fields (PEFs) can be designed to selectively stimulate ECs to alter vascular permeability, and to elucidate the signaling pathways mediating this response. The underlying hypothesis is that PEF will trigger actin stress fiber remodeling in ECs, thereby increasing capillary barrier permeability from translocation of junction proteins with signaling along the Vascular Endothelial Growth Factor Receptor (VEGFR) – adherens junction axis. In Aim 1, the kinetics of barrier function alteration in EC monolayers treated with PEF will be quantified. In Aim 2, the role of VEGFR – cadherin signaling in altering barrier permeability will be evaluated, and potential angiogenic responses studied. In Aim 3, PEF parameters will be designed for selective stimulation of ECs, and then tested for augmenting chemotherapy delivery to tumors. Novel tools and mechanistic investigations that define the signaling mechanisms mediating EC responses to PEF can open several new lines of multidisciplinary investigation and enable major advances in drug delivery.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.