Cephalopod-Inspired Bioelectronic Control of Cellular Signaling

受头足类动物启发的细胞信号生物电子控制

• 批准号: 10246105
• 负责人: Alon A Gorodetsky
• 金额: $ 134.36万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246105
• 关键词: Animals; Biological; Biology; Breathing; Cardiovascular system; Cell Communication; Cell physiology; Cells; Cephalopoda; Clinical; Development; Devices; Disease; Engineering; Foundations; Genetic; Human body; Implant; Length; Ligands; Lipids; Literature; Mediating; Membrane; Metabolic syndrome; Methodology; Musculoskeletal Diseases; Nerve Degeneration; Nucleic Acids; Pathologic; Pathway interactions; Physiological Processes; Play; Production; Proteins; Regulation; Research; Role; Signal Transduction; Skin; Source; Stimulus; Structure; System; Techniques; Technology; Therapeutic; Tissues; Vesicle; Wireless Technology; Work; base; clinical application; clinical diagnostics; clinically relevant; controlled release; extracellular vesicles; genetically modified cells; novel diagnostics; particle; treatment strategy; tumor progression; wound healing

Project Summary/Abstract The ability of cells to efficiently communicate across organismal-level distances and difficult-to-surmount biological barriers is one of the most important fundamental phenomena in biology. A vast body of literature has revealed that such cell-to-cell communication is mediated via membrane-enclosed particles called extracellular vesicles, which are released by cells into their surroundings and contain lipids, ligands, nucleic acids, and proteins. Such extracellular vesicles represent one of the only natural non-viral structures by means of which “source” cells can reprogram the genetics and fate of “target” cells, and as such, they are implicated not only in the regulation of nearly every cellular process but also in the development of nearly every tissue within the human body. Moreover, these vesicles play essential roles in various disease states and pathological conditions, including cancer progression, neurodegeneration, musculoskeletal disorders, cardiovascular degradation, metabolic syndromes, and wound healing. Given their ubiquity and crucial biological roles, extracellular vesicles hold great promise for clinical diagnostics and therapeutics, but to date, such applications have been hindered by key challenges associated with 1) fundamentally understanding extracellular vesicle formation in source cells, 2) loading extracellular vesicles with biomolecular cargo in high yield, 3) controllably regulating extracellular vesicle production with external stimuli, 4) delivering extracellular vesicles to target cells over tissue-relevant length scales, 5) maintaining the long-term biological activity of extracellular vesicle-internalized cargo, and 6) implementing extracellular vesicle-based treatment strategies in living animals. Herein, by drawing inspiration from proteins and structures found in cephalopod skin cells and leveraging the technical foundation established for cephalopod-inspired bioelectronic devices, we propose to solve all of the scientific and technological challenges currently impeding clinical applications of extracellular vesicles. The envisioned research plan involves 1) validating electrical techniques for controlling the release of extracellular vesicles from genetically engineered cells interfaced with different bioelectronic devices and platforms, 2) developing strategies for remotely and wirelessly controlling the release of biomolecular cargo-loaded extracellular vesicles from engineered cells interfaced into implantable bioelectronic systems, and 3) demonstrating that remotely controlled release of clinically valuable cargo-loaded extracellular vesicles by implanted bioelectronic system-integrated source cells can guide target cell fate and tissue development in living animals. Altogether, the successful completion of the proposed work will enable harnessing of extracellular vesicle-mediated cell-to-cell communication pathway for the regulation of physiological processes and will thus furnish transformative opportunities for developing unprecedented next generation diagnostic and therapeutic technologies.

项目概要/摘要 细胞跨有机体水平距离和难以克服的有效通信的能力 生物屏障是生物学中最重要的基本现象之一。大量的文献已经 揭示这种细胞间通讯是通过称为细胞外的膜封闭颗粒介导的 囊泡，由细胞释放到周围环境中，含有脂质、配体、核酸和 蛋白质。这种细胞外囊泡代表了唯一的天然非病毒结构之一，通过它 “源”细胞可以重新编程“目标”细胞的遗传和命运，因此，它们不仅涉及 几乎每个细胞过程的调节，以及人体几乎每个组织发育的调节 身体。此外，这些囊泡在各种疾病状态和病理状况中发挥着重要作用， 包括癌症进展、神经退行性疾病、肌肉骨骼疾病、心血管退化、 代谢综合征和伤口愈合。鉴于其普遍存在和重要的生物学作用，细胞外囊泡 为临床诊断和治疗带来巨大希望，但迄今为止，此类应用受到阻碍 通过与以下相关的关键挑战：1）从根本上了解源细胞中细胞外囊泡的形成， 2) 高产率地向细胞外囊泡装载生物分子货物，3) 可控地调节细胞外囊泡 在外部刺激下产生囊泡，4) 通过组织相关将细胞外囊泡递送至靶细胞 长度尺度，5) 维持细胞外囊泡内化货物的长期生物活性，以及​​ 6) 在活体动物中实施基于细胞外囊泡的治疗策略。在此，通过汲取灵感 来自头足类动物皮肤细胞中发现的蛋白质和结构，并利用已建立的技术基础 对于受头足类动物启发的生物电子设备，我们建议解决所有科学和技术问题 目前阻碍细胞外囊泡临床应用的挑战。设想的研究计划 涉及 1) 验证用于控制遗传性细胞外囊泡释放的电技术 与不同生物电子设备和平台连接的工程细胞，2）制定策略 远程无线控制装载生物分子货物的细胞外囊泡的释放 工程细胞连接到可植入生物电子系统，3）证明远程控制 通过植入的生物电子系统集成释放具有临床价值的装载货物的细胞外囊泡 源细胞可以指导活体动物中靶细胞的命运和组织发育。总而言之，成功的 完成拟议的工作将能够利用细胞外囊泡介导的细胞间相互作用 调节生理过程的通讯途径，从而提供变革性的 开发前所未有的下一代诊断和治疗技术的机会。