CAREER: Modulating endothelial cell function using targeted electrical stimulation

职业：使用靶向电刺激调节内皮细胞功能

• 批准号: 2338949
• 负责人: Govindarajan Srimathveeravalli
• 金额: $ 55.84万
• 依托单位: University of Massachusetts Amherst
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-05-01 至 2029-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2338949&HistoricalAwards=false
• 关键词: CAREER; Modulating; endothelial; cell; function

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.

血管排列血管的内皮细胞在癌症和其他几种非恶性疾病状况中会功能失调，会干扰药物输送，引起感染和阻碍愈合。但是，调节体内特定位置的内皮细胞功能而不将药物注入整个循环是一个主要挑战。这项教师早期职业发展计划（职业）提案的目的是通过使用脉冲电场来开发启动性细胞的技术来解决这一重要问题，这些技术可以使用医疗设备将其传递到人体所需的区域。该项目将研究脉冲电场波形，以对内皮细胞屏障功能进行控制和特定的改变，确定介导这种反应的生物学途径，并测试这种方法以增强药物为肿瘤的药物。从该提案中获得的新工具和知识可以使内皮细胞在各种疾病中的作用并改善数百万癌症患者的治疗结果进行新的研究。该提案中的协同教育和外展活动将开发基于项目的活动，以在本科生和高中生中对使用电力作为一种治疗形式的医疗设备提高认识，并准备进入劳动力或以医疗设备为主题的高等教育。内皮细胞（ECS）衬里血管调节离子通过，在神经和骨骼肌的电刺激过程中，在屏障的传播，发射生物电信号和明显改变的屏障渗透率。尽管如此潜水员的生物电反应，但通常在传统上认为EC是电气令人兴奋的。该提案的研究目标是研究是否可以设计脉冲电场（PEF）来选择性刺激EC以改变血管通透性，并阐明介导该反应的信号传导途径。潜在的假设是，PEF将触发EC中的肌动蛋白应力纤维重塑，从而增加毛细管屏障的渗透性，从沿血管内皮生长因子受体（VEGFR）信号传导的连接蛋白转移到易位的渗透性 - 粘附剂 - 粘附剂轴。在AIM 1中，将量化用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信号传导在改变屏障渗透率中的作用，并研究了潜在的血管生成反应。在AIM 3中，PEF参数将设计用于选择性刺激EC，然后测试以增加化学疗法向肿瘤的递送。定义了介导对PEF的信号机制的新工具和机械调查可以打开多种新的多学科研究，并在药物输送方面取得了重大进展。该奖项反映了NSF的法定任务，并被认为是通过基金会的知识分子和更广泛的影响审查标准来通过评估来通过评估来支持的。