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.

血管内皮细胞在癌症和其他几种非恶性疾病中功能失调，干扰药物输送，引起炎症并阻碍愈合。然而，在体内特定位置调节内皮细胞功能而不将药物输注到整个循环中是一个重大挑战。该教师早期职业发展计划（CAREER）提案的目标是通过开发一种使用脉冲电场靶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输送到身体的所需区域。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，确定介导这种反应的生物学途径，并测试这种方法用于增强药物输送到肿瘤。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推广活动将开发基于项目的活动，以提高本科生和高中生对使用电力作为治疗形式的医疗器械的认识，并为他们进入劳动力市场或接受医疗器械主题的高等教育做好准备。 血管内皮细胞（EC）在神经和骨骼肌的电刺激过程中调节离子的通过，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响应，EC通常不被认为是电兴奋的。本研究的目的是探讨脉冲电场是否可以选择性地刺激内皮细胞改变血管通透性，并阐明介导这种反应的信号通路。潜在的假设是，PEF将触发EC中的肌动蛋白应力纤维重塑，从而增加毛细血管屏障通透性，这是由于连接蛋白的易位，信号沿着血管内皮生长因子受体（VEGFR）-粘附细胞连接轴。在目标1中，将量化用PEF处理的EC单层中屏障功能改变的动力学。在目的2中，将评价VEGFR -钙粘蛋白信号传导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EC，然后测试用于增强对肿瘤的化疗递送。新的工具和机制的调查，定义的信号机制介导的EC响应PEF可以打开多学科的调查，并使药物delivery.This奖项的重大进展反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。