Bioartificial Brain Slices for Drug Screening

用于药物筛选的生物人工脑切片

• 批准号: 8592458
• 负责人: Eric Stephen Guire
• 金额: $ 15.66万
• 依托单位: INNOVATIVE SURFACE TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592458
• 关键词: 3-Dimensional; Acute; Animals; Architecture; Attention deficit hyperactivity disorder; Automation; Biological Assay; Brain; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Characteristics; Clinical; Clinical Trials; Coculture Techniques; Confidential Information; Cost Savings; Coupled; Data; Development; Disease; Electrodes; Electrophysiology (science); Equipment; Foundations; Funding; Generations; Genetic Variation; Glutamates; Gold; Growth; Growth Factor; Hippocampus (Brain); Human; In Situ; Left; Life; Marketing; Measures; Medicine; Mental Depression; Microtomy; Modeling; Modification; Monitor; Mus; Nanotopography; Neural Pathways; Neurons; Neurotransmitters; Outcome; Pain; Parkinson Disease; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Population; Preclinical Drug Evaluation; Preparation; Process; Property; Pyramidal Cells; Rattus; Rodent; Schizophrenia; Slice; Small Business Innovation Research Grant; Spinal Cord; Standard Preparations; Supporting Cell; Surface; Synapses; System; Techniques; Technology; Testing; Thick; Time; Tissue Harvesting; Tissues; Toxin; United States National Institutes of Health; addiction; animal care; brain tissue; cholinergic; clinically relevant; cost; cytotoxicity; cytotoxicity test; design; drug development; extracellular; in vivo; nanofiber; nanoscale; nerve stem cell; nervous system disorder; neural circuit; phase 1 study; postsynaptic; pre-clinical; precursor cell; prototype; public health relevance; relating to nervous system; response; scaffold; sound; tool

DESCRIPTION (provided by applicant): ISurTec is seeking NIH funding to develop a human bioartificial brain slice prototype, designed for use in electrophysiological drug-screening assays. Acute brain slices, prepared from rats or mice, are currently the 'gold standard' preparation for characterizing neural tissue responses to drugs, toxins, or other agents. However, the limited number of brain slices produced per animal, coupled with the high costs of animal care and use, remains a major limitation of this approach. Furthermore, due to interspecies genetic variation, preclinical data acquired through the use of acute brain slices wil usually be of limited predictive power for human clinical trials and postmarket surveillance. In this study, 3-dimensional neural circuit scaffolds will be patterned after the Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus. 350 micron thick scaffolds will be prepared by laminating and annealing random nonwoven and aligned photoreactive nanofiber mats, following their photopatterned surface modification. The resulting bioartificial brain slice scaffolds will establish open field circuit architecture for co- cultured neuronal populations to generate postsynaptic field potentials in response to orthodromic stimulation. In Phase I, prototype scaffolds will be prepared and populated with E18 rat hippocampal neurons, to confirm the scaffold's ability to support the generation of robust postsynaptic field potentials. I Phase II, scaffolds will be populated with human neurons derived from expandable Neural Progenitor (hNP) cell lines. Terminal differentiation of hNPs in situ on growth factor-patterned scaffolds will also be investigated in Phase II. The bioartificial brain slice scaffold will be produced in a standardized format that is compatible with common electrophysiological equipment. Ultimately, we envision the scaffolds will enable electrophysiological assays with high predictive power for multiple neurotransmitter systems including glutamatergic, cholinergic, dopaminergic, and gabaergic synapses. Thus, the human bioartificial brain slice will be a valuable tool for drug development concerning a wide variety of human neurological diseases and disorders, including addiction, ADD/ADHD, depression, Parkinson's disease, pain processing, and schizophrenia. This technology will advance the field of HTS by overcoming two limitations of acute slices derived from rodents (1) limited human relevance and (2) high burden and cost of animal care compliance and oversight.

描述(由申请者提供)：ISurTec正在寻求美国国立卫生研究院的资金，以开发一种用于电生理药物筛选分析的人类生物人工脑片原型。从大鼠或小鼠身上制备的急性脑片，目前是表征神经组织对药物、毒素或其他制剂反应的“黄金标准”准备。然而，每只动物生产的脑片数量有限，再加上动物护理和使用的高昂成本，仍然是这种方法的主要限制。此外，由于物种间的遗传差异，通过使用急性脑片获得的临床前数据通常对人类临床试验和上市后监测的预测能力有限。在这项研究中，三维神经回路支架将模仿Schaffer侧支-CA1锥体细胞突触的海马区。350微米厚的支架将通过对随机非织造布和取向的光反应纳米纤维垫进行光处理表面改性后进行层叠和热处理来制备。由此产生的生物人工脑片支架将为共培养的神经元群体建立开场电路结构，以产生突触后场电位以响应顺向刺激。在第一阶段，将准备原型支架并填充E18大鼠海马神经元，以确认支架支持产生强大的突触后场电位的能力。在第二阶段，支架上将植入来自可扩展神经前体细胞系(HNP)的人类神经元。第二阶段还将研究hNPs在生长因子图案支架上的末端分化。生物人工脑片支架将以与常见电生理设备兼容的标准化格式生产。最终，我们设想这种支架将能够对多种神经递质系统进行高预测能力的电生理分析，包括谷氨酸能、胆碱能、多巴胺能和GABA能突触。因此，人类生物人工脑片将成为治疗各种人类神经疾病和障碍的宝贵工具，包括成瘾、ADD/ADHD、抑郁症、帕金森氏病、疼痛处理和精神分裂症。这项技术将通过克服来自啮齿动物的急性切片的两个限制(1)有限的人类相关性和(2)动物护理合规和监督的高负担和成本，从而推动高温超导领域的发展。