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: 9892391
• 负责人: Gabriela Romero Uribe
• 金额: $ 17.65万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892391
• 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; Wireless Technology; 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 stimulation; neuroregulation; neurotransmission; novel; optoacoustic tomography; optogenetics; personalized medicine; photoacoustic imaging; plasmonics; relating to nervous system; repaired; response; side effect; tissue phantom

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.

项目摘要/摘要 细胞类型对神经回路的特异性操纵是需要治疗神经系统疾病（例如 癫痫和自闭症。现有的控制神经活动的技术提供了有限的可能性。操纵 通过直接药物治疗的脑电路受到血脑屏障的选择性渗透性的限制， 脑液体的快速清除和缺乏特异性，这导致对药物的反应不佳 不良副作用。电刺激和光遗传学开放了修复神经的可能性 通过直接控制大脑电路动力学的功能障碍。但是，这两种技术都需要植入 损害生物组织的设备。最近，纳米材料的热量耗散，特别是 磁性纳米颗粒（MNP）和等离子纳米结构已提出用于无线控制 使用外部刺激的细胞信号传导。弱磁性特性和组织的低电导率 允许交替的磁场（AMF）深入体内，从而使MNPS加热 特别有希望治疗脑疾病。这项研究赠款将开发出一种新颖的无线 取决于MNP的加热效应的药理大脑调制方法释放 来自MNPs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缀合物 （GNRS）用于光声断层扫描（PAT）指导的，磁热控制的神经调节释放 化合物。初步结果证明：1）MNPS在AMF下散发的热量足以满足 从MNP表面完全释放有效载荷，2）通过抗体靶向神经元膜的MNP 特异性，然后进行磁热药物治疗，允许神经活动激发，3） 从MNP表面对聚合物生长的精确控制。这项研究赠款推动了刺激的新进步 用于神经活动的个性化药理学调节的响应式杂化纳米颗粒系统。无线的 多巴胺和氯丙嗪从聚合物涂层的MNP中的磁热释放有望激发，并且 抑制多巴胺能神经元的活性。利用GNRS介导的PAT，该系统将是 通过使用AMF触发热响应，以多种剂量定制以按需释放。最后， 将评估通过磁热药物释放临床上相关的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希望 作为一种强大的药理学技术，可用于恢复大脑功能，并在单细胞中 操纵设置，以更好地理解神经回路。这项工作的未来方向包括 开发磁透光平台，该平台允许体内pat监测的药理学调节 神经活动。