A Closed Loop Control System with Live Cells in the Loop

循环中带有活细胞的闭环控制系统

• 批准号: 9978534
• 负责人: Francesco Sorrentino
• 金额: $ 18万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978534
• 关键词: Affect; Aging; Autophagocytosis; Biological; Biological Sciences; Cell Line; Cell physiology; Cells; Cellular Stress; Centers of Research Excellence; Combination Drug Therapy; Coupled; Development; Diabetes Mellitus; Disease; Dose; Down-Regulation; Engineering; Environment; Experimental Models; Faculty; Flow Cytometry; Fluorescence Microscopy; Gap Junctions; Goals; Homeostasis; Image; Immune; In Vitro; Individual; Infection; Inflammation; Inflammatory; Insulin; Intervention; Investigation; Knowledge; Lead; Liquid substance; Mathematics; Measurement; Medical; Mentors; Metabolism; Methods; Modeling; Nerve Degeneration; New Mexico; Nutrient; Optics; Outcome; Output; Patients; Performance; Personal Satisfaction; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Physiological Processes; Positioning Attribute; Probability; Process; Reagent; Regulation; Research; Role; Sampling; Schedule; Science; Scientific Advances and Accomplishments; Signal Transduction; Specialist; System; Systems Analysis; Techniques; Technology; Testing; Therapeutic; Thinking; Time; Toxic effect; Uncertainty; Universities; Up-Regulation; Vesicle; Work; base; biological systems; control theory; design; dosage; experimental study; improved; infancy; innovation; instrument; mathematical model; member; model design; response; success; therapy resistant; treatment optimization

A CLOSED LOOP CONTROL SYSTEM WITH LIVE CELLS IN THE LOOP This work proposes to develop and apply, for the first time, control theory-derived strategies to regulate autophagy in live cells using an innovative experimental testbed with sensing and actuating capabilities. Combinations of pharmacological interventions are used extensively for the treatment of many diseases. Therefore, there is significant potential for control theory- based treatments to enhance the well-being of patients through careful tuning of dosage delivery of multiple pharmacological reagents (PRs). Intracellular measurements of the formation of autophagy vesicles (AVs) in response to the application of various PRs will be conducted using traditional fluorescence microscopy and an Amnis ImageStream Mark II Imaging Flow Cytometer, available at the University of New Mexico (UNM) Autophagy, Inflammation, and Metabolism in Disease Center of Biomedical Research Excellence (AIM Center), the only autophagy-focused CoBRE in the nation and in which PI Sorrentino is an Associate Member. This state-of-the-art instrument uses flow cytometry and multispectral imaging to detect intracellular AVs, providing an accurate count of total AVs (the output) within individual cells. A perfusive fluidic delivery system to deliver drugs (the inputs) in time and in a controlled manner will be developed as part of the proposed effort. This experimental testbed will provide a proof-of-concept realization of closed-loop control of autophagy in live-cell experiments. In addition, an integrated mathematical model will be developed to describe the regulation of autophagy in live cells by considering the effects of several PRs on the formation of AVs. Our control decisions will be explicated at two levels: first, the choice of PRs to use in a combination study out of a set of available PRs; and second, the dosage function for each PR in the combination, i.e., the rate at which the PR is supplied as a function of time, with time being a continuous function. An innovative multi-scenario optimal controller will also be developed and tested to optimize the control actions in the presence of limited experimental information and uncertainty about the state of the system. The UNM AIM Center hosts a team of specialists who conduct groundbreaking research into the role of autophagy in inflammatory diseases and infection, and who provide mentoring opportunities for junior faculty. As an Associate Member of the AIM Center, PI Sorrentino is in a unique position within a specialized, local environment to meet with success. The long-term impact of the proposed research will be significant, as it has considerable potential to advance scientific knowledge at the nexus of engineering and life sciences, and lead to the development of optimized therapies that could positively affect the well-being of millions of patients worldwide. 1

环路中有活细胞的闭环控制系统 这项工作提出首次开发和应用控制理论衍生的策略来调节活体自噬 使用具有传感和驱动能力组合的创新实验测试台来测试细胞。 干预措施主要用于治疗许多疾病，因此，控制理论具有巨大的潜力。 通过仔细调整多种药理学的剂量输送，以增强患者的健康为基础的治疗 响应应用的自噬囊泡 (AV) 形成的细胞内测量。 各种 PR 将使用传统荧光显微镜和 Amnis ImageStream Mark II 成像进行 流式细胞仪，可在新墨西哥大学 (UNM) 购买 疾病中的自噬、炎症和代谢 生物医学卓越研究中心（AIM 中心）是全国唯一专注于自噬的 CoBRE，其中 PI Sorrentino 是一名准会员。这款最先进的仪器使用流式细胞术和多光谱成像技术。 检测细胞内 AV，提供单个细胞内总 AV（输出）的准确计数。 作为拟议项目的一部分，将开发及时并以受控方式输送药物（输入）的输送系统 该实验平台将提供活细胞自噬闭环控制的概念验证实现。 此外，还将开发一个综合数学模型来描述自噬的调节。 通过考虑多个 PR 对 AV 形成的影响，我们的控制决策将在两个方面进行说明。 水平：首先，从一组可用的 PR 中选择用于联合研究的 PR；其次，剂量函数； 对于组合中的每个 PR，即，提供 PR 的速率作为时间的函数，其中时间是连续的 还将开发和测试创新的多场景最优控制器，以优化控制动作。 有限的实验信息和系统状态的不确定性。 新墨西哥大学 AIM 中心拥有一支专家团队，他们对自噬在细胞中的作用进行了开创性的研究。 炎症性疾病和感染，并为初级教师提供指导机会。 作为 AIM 中心的一员，PI Sorrentino 在专业化的当地环境中处于独特的地位，能够取得成功。 拟议研究的长期影响将是重大的，因为它具有推进科学知识的巨大潜力 工程和生命科学的结合，并导致优化疗法的开发，这些疗法可以积极影响 全球数百万患者的福祉。 1