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Solid-state patch clamp platform to diagnose autism and screen for effective drug

用于诊断自闭症和筛选有效药物的固态膜片钳平台

基本信息

批准号：
8701413
负责人：
John R Huguenard
金额：
$ 23.03万
依托单位：
STANFORD UNIVERSITY
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：
2013-07-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701413
关键词：
22q13.3 Affect Architecture Autistic Disorder Behavioral Symptoms Biological Sciences Biology Biomedical Engineering Cells Child Clinical Communities Complex Coupled Data Set Development Devices Diagnosis Diagnostic Diagnostics Research Differentiation and Growth Disease Down Syndrome Effectiveness Electrodes Electrophysiology (science)Engineering Equilibrium Family Fibroblasts Functional disorder Generations Genes Genetic Glass Goals Hippocampus (Brain)Human Individual Measurement Measures Medicine Membrane Mental disorders Methodology Methods Microfabrication Mutate Mutation Nanotechnology Neurodevelopmental Disorder Neurons Patients Pharmaceutical Preparations Pharmacotherapy Phase Population Preclinical Drug Evaluation Process Property Research Personnel Schizophrenia Scientist Skin Staging Stereotyped Behavior Synapses Syndrome System Technology Therapeutic Tissues Triad Acrylic Resin United States Universities Whole-Cell Recordings Work autism spectrum disorder base cost design drug candidate effective therapy high throughput screening induced pluripotent stem cell innovation loss of function nanofabrication patch clamp programs public health relevance screening small molecule social communication impairment solid state synaptic function tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASDs) have risen to approximately 1 in 88 in the Unites States over the past years, affecting an entire generation of children, families and communities. Currently, the diagnosis for most forms of ASD is based on a triad of behavioral symptoms, including social impairments, communication difficulties, and repetitive or stereotyped behaviors, with no quantitative measures for screening or assessment of potential drug therapies. Electrophysiological measurements of synapses and neuronal networks from these patients may hold the potential for diagnosing, characterizing and analyzing the effectiveness of potential treatment strategies. Here, we propose to apply a transformative technology for the long-term intracellular recording networks of neurons differentiated from patient-derived iPSC. To accomplish this goal, we have created a solid-state device comprised of 2D arrays of Stealth electrodes that sit passively within the membrane of neuronal cells and have the capacity to record synaptic, neuronal and network properties of multiple interconnected neurons simultaneously for days to weeks. Through the optimization of the fabrication of these Stealth probes and the transformation into a turn-key device, we will evaluate the feasibility of this platform as a diagnostic and research tool for ASD. We then propose to use this innovative scalable analytical platform to characterize the neuronal, synaptic and network signatures of neurons differentiated from iPS cells derived from patients with Phelan-McDermid Syndrome and then assess the effectiveness of emerging drug therapies to normalize aberrant signatures. If successful, our solid-state platform can be transformed into a high-throughput screening device that will allow investigators to recapitulate early developmental stages of ASD and evaluate the effects of ASD mutations and environmental insults on neuronal network and synaptic function and utilize this as a tool for drug screening, diagnosis and personalized treatment.

描述（由申请人提供）：在过去的几年里，自闭症谱系障碍（ASD）在美国已经上升到大约1/88，影响了整整一代儿童，家庭和社区。目前，大多数形式的ASD的诊断是基于行为症状的三重性，包括社交障碍，沟通困难和重复或刻板行为，没有定量措施来筛选或评估潜在的药物治疗。这些患者的突触和神经元网络的电生理测量可能具有诊断、表征和分析潜在治疗策略的有效性的潜力。在这里，我们建议将一种变革性技术应用于从患者来源的iPSC分化的神经元的长期细胞内记录网络。为了实现这一目标，我们已经创建了一个由2D隐形电极阵列组成的固态设备，这些电极被动地位于神经元细胞的膜内，并且能够同时记录多个相互连接的神经元的突触，神经元和网络特性数天至数周。通过优化这些隐形探头的制造和转换成交钥匙设备，我们将评估该平台作为ASD诊断和研究工具的可行性。然后，我们建议使用这种创新的可扩展的分析平台来表征从来自McDermid综合征患者的iPS细胞分化的神经元的神经元，突触和网络特征，然后评估新兴药物治疗的有效性，以使异常特征正常化。如果成功，我们的固态平台可以转化为高通量筛选设备，使研究人员能够重现ASD的早期发育阶段，并评估ASD突变和环境损伤对神经元网络和突触功能的影响，并将其用作药物筛选，诊断和个性化治疗的工具。