Non-invasive, Transgene-free, on-demand Pharmacological Modulation of Neural Activity

非侵入性、非转基因、按需药理调节神经活动

• 批准号: 10322083
• 负责人: Gabriela Romero Uribe
• 金额: $ 21.4万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322083
• 关键词: 3-Dimensional; Address; Antibodies; Antibody Specificity; Biological; Brain; Brain Diseases; Brain Mapping; Calcium ion; Cells; Cerebrum; Chemicals; Chemistry; Chlorpromazine; Complex; Corpus striatum structure; Custom; Dependence; Detection; Development; Dopamine; Drug Controls; Electric Conductivity; Electric Stimulation; Engineering; Epilepsy; Feedback; Future; Gold; Growth; Heating; Hybrids; Liquid substance; Magnetic nanoparticles; Magnetism; Mediating; Membrane; Modeling; Modification; Monitor; Nanoconjugate; Nanostructures; Nature; Neural Inhibition; Neuronal Dysfunction; Neurons; Oligonucleotides; Patch-Clamp Techniques; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phosphoproteins; Polymers; Population; Process; Property; Rattus; Reporting; Research Project Grants; Signal Transduction; Specificity; Stimulus; Surface; System; Techniques; Technology; Temperature; Time; Tissues; Transgenes; Translations; Work; autism spectrum disorder; base; biocompatible polymer; blood-brain barrier permeabilization; brain tissue; cell type; clinical translation; clinically relevant; combinatorial; controlled release; design; dopaminergic neuron; dosage; effectiveness validation; ethylene glycol; fluorescence imaging; image guided; implantable device; improved; in vitro Model; in vitro activity; in vivo; iron oxide; magnetic field; mind control; nanomaterials; nanoparticle; nanorod; nanoscale; nervous system disorder; neural circuit; neural network; neural repair; neural stimulation; neuroregulation; neurotransmission; novel; optoacoustic tomography; optogenetics; personalized medicine; photoacoustic imaging; plasmonics; relating to nervous system; response; side effect; tissue phantom; wireless

PROJECT SUMMARY/ABSTRACT Cell-type specific manipulation of neural circuits is required for the treatment of neurological disorders such as epilepsy and autism. Existing technologies to control neural activity offer limited possibilities. Manipulation of brain circuits via direct drug treatment is restricted by the selective permeability of the blood-brain barrier, the rapid clearance of cerebral fluids and the lack of specificity, which results in poor response to drugs and undesirable side effects. Electrical stimulation and optogenetics have open the possibility of repairing neural dysfunction through direct control of brain circuit dynamics. However, both technologies require implantable devices that are damaging to biological tissues. Recently, the heat dissipation by nanomaterials, particularly magnetic nanoparticles (MNPs) and plasmonic nanostructures, has been proposed for the wireless control of cellular signaling using external stimuli. The weak magnetic properties and low electrical conductivity of tissue allow alternating magnetic fields (AMFs) to reach deep into the body, making hysteresis heating of MNPs particularly promising for the treatment of brain disorders. This research grant will develop a novel wireless pharmacological brain modulation approach that depends on MNPs heating effects to release neuromodulatory compounds from temperature-sensitive polymers grafted on the surface of MNPs. Additionally, we will fabricate a nanoconjugate composed of surface engineered MNPs and gold nanorods (GNRs) for photoacoustic tomography (PAT)-guided, magnetothermally-controlled release of neuromodulatory compounds. Preliminary results demonstrate: 1) the heat dissipated by MNPs under AMFs is sufficient for the complete release of a payload from MNP surfaces, 2) MNPs targeting to neuronal membranes via antibody specificity, followed by magnetothermal drug treatment that allows for excitation of neural activity, and 3) the precise control of polymer growth from the surface of MNPs. This research grant drives new advances in stimuli- responsive hybrid nanoparticle systems for personalized pharmacological modulation of neural activity. Wireless magnetothermal release of dopamine and chlorpromazine from polymer coated MNPs is expected to excite and inhibit activity of dopaminergic neurons. Taking advantage of GNRs-mediated PAT, this system will be customized for on-demand release in multiple dosages by triggering heat response with AMFs. Finally, the functional properties of clinically-relevant neural modulation by magnetothermal drug release will be evaluated through in vitro models and rat brains. Magnetothermal modulation of neural activity shows considerable promise as a powerful pharmacological technology that can be applied to restore brain functions, and in single-cell manipulation settings for the better understanding of neural circuits. Future directions of this work include the development of a magnetothermal platform that allow in vivo PAT-monitored pharmacological modulation of neural activity.

项目概要/摘要 治疗神经系统疾病需要对神经回路进行细胞类型特异性操作，例如 癫痫和自闭症。现有的控制神经活动的技术提供的可能性有限。操纵 通过直接药物治疗的脑回路受到血脑屏障的选择性通透性的限制， 脑液清除速度快且缺乏特异性，导致对药物和药物反应不佳 不良副作用。电刺激和光遗传学开启了修复神经的可能性 通过直接控制大脑回路动态来实现功能障碍。然而，这两种技术都需要植入式 损坏生物组织的设备。近年来，纳米材料的散热，特别是 磁性纳米粒子（MNP）和等离子体纳米结构，已被提议用于无线控制 使用外部刺激的细胞信号传导。组织的弱磁性和低电导率 允许交变磁场 (AMF) 深入人体，使 MNP 产生磁滞加热 对于治疗脑部疾病特别有希望。该研究经费将开发一种新型无线 依赖 MNP 加热效应释放的药理脑调节方法 来自接枝在 MNP 表面的温度敏感聚合物的神经调节化合物。 此外，我们将制造由表面工程 MNP 和金纳米棒组成的纳米复合物 （GNR）用于光声断层扫描（PAT）引导的磁热控制神经调节释放 化合物。初步结果表明：1）AMF 下 MNP 散发的热量足以满足 从 MNP 表面完全释放有效负载，2) MNP 通过抗体靶向神经元膜 特异性，然后进行磁热药物治疗，以激发神经活动，以及 3) 精确控制聚合物从 MNP 表面的生长。这项研究资助推动了刺激方面的新进展 用于个性化药理学调节神经活动的响应性混合纳米颗粒系统。无线的 从聚合物涂层的 MNP 中磁热释放多巴胺和氯丙嗪预计会激发和 抑制多巴胺能神经元的活性。利用 GNR 介导的 PAT，该系统将 通过 AMF 触发热响应，可定制为多种剂量的按需释放。最后， 将评估磁热药物释放的临床相关神经调节的功能特性 通过体外模型和大鼠大脑。神经活动的磁热调节显示出巨大的前景 作为一种强大的药理技术，可用于恢复大脑功能，并且在单细胞中 操作设置可以更好地理解神经回路。这项工作的未来方向包括 开发磁热平台，允许体内 PAT 监测的药理调节 神经活动。