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（由申请人提供）：ISurTec 正在寻求 NIH 资金来开发人类生物人工脑切片原型，设计用于电生理药物筛选测定。从大鼠或小鼠身上制备的急性脑切片是目前表征神经组织对药物、毒素或其他制剂反应的“金标准”制剂。然而，每只动物产生的脑切片数量有限，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，由于种间遗传变异，通过使用急性脑切片获得的临床前数据通常对人体临床试验和上市后监测的预测能力有限。在这项研究中，3维神经回路支架将按照海马的 Schaffer 侧支 CA1 锥体细胞突触进行图案化。 350微米厚的支架将通过层压和退火随机非织造布和排列的光反应性纳米纤维垫，并在其光图案化表面改性后制备。由此产生的生物人工脑切片支架将为共培养的神经元群体建立开放场电路架构，以响应顺向刺激而产生突触后场电位。在第一阶段，将制备原型支架并填充 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。 I 期 II 期，支架将填充源自可扩展神经祖细胞 (hNP) 细胞系的人类神经元。第二阶段还将研究 hNP 在生长因子图案化支架上原位的终末分化。生物人工脑切片支架将以标准化格式生产，与常见的电生理设备兼容。最终，我们设想这些支架将使电生理学分析成为可能，对多种神经递质系统（包括谷氨酸能、胆碱能、多巴胺能和伽巴能突触）具有高预测能力。因此，人类生物人工脑切片将成为药物开发的宝贵工具，涉及多种人类神经系统疾病和紊乱，包括成瘾、ADD/ADHD、抑郁症、帕金森病、疼痛处理和精神分裂症。这项技术将克服啮齿类动物急性切片的两个局限性，从而推动 HTS 领域的发展：(1) 人类相关性有限；(2) 动物护理合规和监督的高负担和成本。