Nanoparticle Induced Circuit Excitation

纳米颗粒感应电路激励

基本信息

批准号：
8338787
负责人：
JEFFREY M FRIEDMAN
金额：
$ 37.98万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-26 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338787
关键词：
Action Potentials Address Animals Antibodies Apoptosis Autologous Transplantation Basic Science Behavior Binding Biology Biotin Brain Calcium Cell physiology Cell surface Cells Clinical Communities Complex Coupled Cultured Cells DNA Structure Data Desire for food Diabetic mouse Disadvantaged Distant Electromagnetic Fields Endocrine Energy Metabolism Ensure Epitopes Exposure to Feeding behaviors Fiber Optics Foundations Frequencies Gene Expression Gene Expression Regulation Glucagon Glucose Glycocalyx Goals Gold Heating Hippocampus (Brain)Hormones Human Hypothalamic structure Image In Vitro Individual Injection of therapeutic agent Insulin Internal Ribosome Entry Site Investigation Ion Channel Lead Life Light Luciferases Membrane Membrane Potentials Metals Methodology Methods Mitochondria Modeling Monitor Neurons Nude Mice Operative Surgical Procedures Optical Methods Organism Peripheral Physiological Physiological Processes Physiology Plasma Play Population Process Proteins Protocols documentation Relative (related person)Reporter Response Elements Rewards Rhodopsin Role Safety Slice Staging Streptavidin Structure of nucleus infundibularis hypothalami System TRPV1 gene Techniques Technology Temperature Testing Time Transgenic Mice base blood glucose regulation cell type cellular engineering combinatorial diabetic dopaminergic neuron ferrous oxide glucose metabolism implantation in vivo induced pluripotent stem cell insulin secretion iron oxide mouse model nanoparticle new technology novel strategies particle patch clamp promoter radiofrequency relating to nervous system research study response tool tumor

项目摘要

DESCRIPTION (provided by applicant): A set of experiments is proposed to validate and further develop a new nanoparticle based technology, Nanoparticle induced Circuit excitation (NICE), for modulating the activity of cells remotely and non-invasively. A fundamental goal of biology is to understand the role of each cell type in a complex organism. The definitive test of cell function is to selectively turn on or off the activity of a single cell type in a living animal and examine the effect on physiological function. Recent tools, such as light activated ion channels such as channel rhodopsin, have pioneered the external control of membrane potential in genetically defined cells and established a new means for investigation by neuroscientists. However, these optical methods have practical disadvantages limiting their application including the need for surgical implantation of invasive fiber optics; the inability to stimulate cells in multiple anatomical regions simultaneously; and the difficulty of modulating multiple cell types in parallel. We address this challenge by using nanoparticles to activate defined cell populations remotely with radiowaves. Ferrous oxide coated with streptavidin is used to decorate cells, which express a biotin acceptor protein under the control of cell specific promoters. These same cells are engineered to also express TRPV1, a single component, temperature-sensitive ion channel that can detect small changes in temperature within the physiological range and by conformational change allow graded calcium entry. Exposing the metal coated cells to a defined electromagnetic field increases the local temperature and activates TRPV1 channels resulting in a Ca2+ current and cell activation. We have preliminary data that confirms the efficacy of this method in vitro and now propose to extend our studies to further validate the technology in vitro and to modulate in vivo functions such as hormone release and neural activity. We will also establish a means for combinatorial activation of different cells using a modified TRPV1 and nanoparticles fabricated from other metals that can be excited at different wavelengths. We will use this tool to examine the roles of specific peripheral and CNS cell populations in energy metabolism. We propose to develop this method in three stages: 1) Validate the safety and utility of NICE in vitro and refine the methodology by decorating different cell types with distinct particles tuned to different wavelengths to activate ensembles of different cell populations in various combinations. 2) Establish the ability of NICE to modify hormone release to regulate glucose metabolism in diabetic animals in vivo. 3) Show that NICE can be used to stimulate action potentials in electrically excitable cells to modify behavior and use NICE to investigate the role of specific hypothalamic populations in (NPY and POMC) to control appetite. In time, NICE may be adapted for clinical uses, e.g: induced pluripotent stem cells engineered to express NICE constructs may act as autografts to enable external control of cell function. These applications are distant but not inconceivable and the studies proposed may form the foundation for the clinical use of nanoparticles.

描述（由申请人提供）：提出了一组实验来验证和进一步开发基于纳米颗粒的新技术，纳米颗粒诱导电路激励（NICE），用于远程和非侵入性地调节细胞的活动。生物学的一个基本目标是了解每种细胞类型在复杂生物体中的作用。细胞功能的最终测试是选择性地开启或关闭活体动物中单一细胞类型的活性，并检查其对生理功能的影响。最近的工具，例如光激活离子通道（如通道视紫红质），率先在基因定义的细胞中对膜电位进行外部控制，并为神经科学家的研究建立了一种新方法。然而，这些光学方法具有限制其应用的实际缺点，包括需要通过手术植入侵入性光纤；无法同时刺激多个解剖区域的细胞；以及并行调节多种细胞类型的难度。我们通过使用纳米颗粒通过无线电波远程激活特定的细胞群来应对这一挑战。涂有链霉亲和素的氧化亚铁用于装饰细胞，该细胞在细胞特异性启动子的控制下表达生物素受体蛋白。这些相同的细胞也被设计成表达 TRPV1，这是一种单一成分、温度敏感的离子通道，可以检测生理范围内温度的微小变化，并通过构象变化允许分级钙进入。将金属涂层细胞暴露于特定的电磁场会增加局部温度并激活 TRPV1 通道，从而产生 Ca2+ 电流和细胞激活。我们有初步数据证实了这种方法在体外的有效性，现在建议扩展我们的研究，以进一步验证体外技术并调节体内功能，例如激素释放和神经活动。我们还将建立一种使用改良的 TRPV1 和由其他金属制成的纳米颗粒组合激活不同细胞的方法，这些纳米颗粒可以在不同的波长下激发。我们将使用这个工具来检查特定外周和中枢神经系统细胞群在能量代谢中的作用。我们建议分三个阶段开发这种方法：1）在体外验证 NICE 的安全性和实用性，并通过用调整到不同波长的不同颗粒装饰不同的细胞类型来完善方法，以激活不同组合中不同细胞群的集合。 2）建立NICE改变激素释放以调节糖尿病动物体内葡萄糖代谢的能力。 3）表明NICE可用于刺激可电兴奋细胞的动作电位以改变行为，并使用NICE研究特定下丘脑群体（NPY和POMC）控制食欲的作用。随着时间的推移，NICE 可能会适应临床用途，例如：经过工程改造以表达 NICE 构建体的诱导多能干细胞可以充当自体移植物，以实现细胞功能的外部控制。这些应用虽然遥远，但并非不可想象，所提出的研究可能为纳米颗粒的临床应用奠定基础。