CAREER: Modulating endothelial cell function using targeted electrical stimulation

在癌症和其他几种非恶性疾病中，排列血管的内皮细胞功能失调，干扰药物输送，导致炎症和阻碍愈合。然而，在不将药物注入整个循环的情况下调节体内特定位置的内皮细胞功能是一个重大挑战。该学院早期职业发展计划(Career)建议的目标是通过开发一种使用脉冲电场定向刺激内皮细胞的技术来解决这一重要问题，该技术可以使用医疗设备传递到身体的所需区域。该项目将研究能够控制和特异性改变内皮细胞屏障功能的脉冲电场波形，确定介导这一反应的生物路径，并测试这一方法以增强对肿瘤的药物输送。从这项提议中获得的新工具和知识可以使人们能够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。该提案中的协同教育和推广活动将开展以项目为基础的活动，在本科生和高中生中培养他们对将电作为一种治疗形式的医疗器械的认识，并为他们进入劳动力大军或接受关于医疗器械主题的高等教育做好准备。血管内皮细胞调节离子通道，传递生物电信号，并在电刺激神经和骨骼肌时表现出屏障通透性的改变。尽管有如此多样的生物电反应，但传统上并不认为内皮细胞是电兴奋的。该方案的研究目的是探讨脉冲电场(PEF)能否选择性刺激内皮细胞改变血管通透性，并阐明介导这一反应的信号通路。潜在的假设是，PEF将触发内皮细胞肌动蛋白应激纤维重塑，从而增加连接蛋白转位的毛细血管屏障通透性，并沿着血管内皮生长因子受体(VEGFR)-黏附连接轴传递信号。在目标1中，将量化经脉冲电场处理的EC单层屏障功能改变的动力学。在目标2中，将评估VEGFR-钙粘素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。在目标3中，PEF参数将被设计用于选择性刺激内皮细胞，然后测试以增加对肿瘤的化疗输送。定义EC对PEF反应的信号机制的新工具和机制调查可以开辟多学科调查的几条新路线，并使药物输送方面取得重大进展。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.