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，在不将药物注入整个循环的情况下调节体内特定部位的内皮细胞功能是可行的。该学院早期职业发展计划（CAREER）提案的目标是通过开发一种使用脉冲电场定向刺激内皮细胞的技术来解决这一重要问题。该项目将研究脉冲电场波形，以控制和特定地改变内皮细胞屏障功能，确定介导这种反应的生物途径，并测试这种增强肿瘤药物输送的方法。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。该提案中的协同教育和外展活动将开展基于项目的活动，以提高对内皮细胞的认识。本科和高中向学校学生介绍使用电作为治疗形式的医疗设备，并为他们进入劳动力市场或接受有关医疗设备的高等教育做好准备。血管内壁的内皮细胞 (EC) 调节离子的通道，传输生物电信号。 ，并且在神经和骨骼肌的电刺激过程中明显改变了屏障通透性，尽管生物电反应多种多样，但传统上并不认为 EC 具有电兴奋性。本提案的研究目的是研究脉冲电场是否具有电兴奋性。 (PEF) 可被设计为选择性刺激 EC 来改变血管通透性，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，从而通过连接蛋白的易位增加毛细血管屏障通透性。沿着血管内皮生长因子受体 (VEGFR) 的信号传导 - 粘附连接轴 在目标 1 中，EC 屏障功能改变的动力学。在目标 2 中，将评估 VEGFR-钙粘蛋白信号在改变屏障通透性中的作用，并在目标 3 中研究潜在的血管生成反应，然后设计 PEF 参数以选择性刺激 EC。经测试可增强对肿瘤的化疗递送，这些新工具和机制研究定义了介导 EC 对 PEF 反应的信号机制，可以开辟多学科研究的新领域，并促进药物的重大进展。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。