Bioartificial Brain Slices for Drug Screening

用于药物筛选的生物人工脑切片

基本信息

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
项目类别：
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

项目摘要

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资金来开发人工生物型脑切片原型，该原型用于电生理药物筛查测定法。目前，由大鼠或小鼠制备的急性脑切片是表征对药物，毒素或其他药物的神经组织反应的“金标准”准备。但是，每只动物产生的脑切片数量有限，再加上动物护理和使用的高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而获得的临床前数据通常对人类临床试验和后市场监测的预测能力有限。在这项研究中，将在海马的Schaffer Collateral-CA1锥体细胞突触之后对三维神经回路支架进行图案。在其光模式的表面修饰之后，将制备350微米厚的脚手架，通过层压和退火随机非编织和对齐的光电反应性纳米纤维垫。由此产生的生物人工脑切片支架将建立共同培养的神经元种群的开放式电路结构，以响应正质刺激而产生突触后场电位。在第一阶段，将准备原型支架，并用E18大鼠海马神经元填充，以确认支架支持强大突触后场电位的产生的能力。 I第二阶段，支架将被源自可扩展神经祖细胞（HNP）细胞系的人类神经元填充。在II阶段，也将研究HNP的原位终末分化。生物人工脑切片支架将以标准化格式生产，该格式与常见的电生理设备兼容。最终，我们设想脚手架将使多个神经递质系统具有高预测能力的电生理测定，包括谷氨酸能，胆碱能，多巴胺能和GABA能突触。因此，人造的人工脑切片将成为有关药物开发的宝贵工具，这些工具涉及各种各样的人类神经系统疾病和疾病，包括成瘾，ADD/ADHD，抑郁症，帕金森氏病，帕金森氏病，疼痛处理和精神分裂症。这项技术将通过克服从啮齿动物衍生的急性切片的两个限制（1）人类相关性和（2）动物护理依从性和监督的高负担和成本来推动HTS领域。