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，以验证并进一步开发基于纳米颗粒的新技术，即纳米颗粒诱导的电路激发（NICE），以远程和非侵入性调节细胞的活性。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。细胞功能的确定测试是选择性地打开或关闭活动物中单细胞类型的活性，并检查对生理功能的影响。最近的工具，例如光活化的离子通道，例如通道视紫红蛋白，率先控制了遗传定义的细胞中膜电位的外部控制，并建立了神经科学家研究的新方法。但是，这些光学方法具有限制其应用的实际缺点，包括需要手术植入侵入性光纤光学元件；无法同时刺激多个解剖区域的细胞；以及并行调节多种单元格类型的困难。我们通过使用纳米颗粒用放射线端远程激活定义的细胞群来应对这一挑战。涂有链霉亲和素的亚铁氧化物用于装饰细胞，在细胞特异性启动子的控制下表达生物素受体蛋白。这些相同的单元格被设计为表达TRPV1，即单个成分，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逐渐成分的钙进入。将金属涂层细胞暴露于定义的电磁场会增加局部温度，并激活TRPV1通道，从而导致Ca2+电流和细胞激活。我们拥有初步数据，可以证实该方法在体外的功效，现在建议扩展我们的研究以进一步验证体外验证技术并调节体内功能，例如激素释放和神经活动。我们还将使用从其他金属制造的改良的TRPV1和纳米颗粒建立一种方法，以在不同的波长上激发。我们将使用此工具来检查特定的外围和中枢神经系统细胞群在能量代谢中的作用。我们建议在三个阶段开发这种方法：1）通过用不同的粒子装饰不同的细胞类型，以不同的粒子调谐到不同波长，以激活各种组合中不同细胞群体的集合，从而验证NICE体外的安全性和实用性。 2）建立良好修饰激素释放以调节体内糖尿病动物中葡萄糖代谢的能力。 3）表明，NICE可用于刺激电气激发细胞中的动作电位，以改变行为，并使用NICE研究（NPY和POMC）在控制食欲中的特定下丘脑种群的作用。随着时间的流逝，可以将NICE改编成临床用途，例如：诱导的多能干细胞设计用于表达良好构建体的干细胞可以充当自体移植，以使细胞功能的外部控制。这些应用是遥远的，但不可思议，提出的研究可能构成纳米颗粒临床使用的基础。