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

• 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
• 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

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）：过去几年，美国自闭症谱系障碍 (ASD) 已上升至大约每 88 人中就有 1 人患有自闭症谱系障碍，影响了整整一代儿童、家庭和社区。目前，大多数形式的自闭症谱系障碍的诊断都是基于三联症行为症状，包括社交障碍、沟通困难以及重复或刻板行为，没有用于筛选或评估潜在药物疗法的定量措施。对这些患者的突触和神经元网络进行电生理学测量可能具有诊断、表征和分析潜在治疗策略有效性的潜力。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 分化而来的神经元的长期细胞内记录网络。为了实现这一目标，我们创建了一种由二维隐形电极阵列组成的固态设备，该电极被动地位于神经元细胞膜内，能够在数天到数周内同时记录多个互连神经元的突触、神经元和网络特性。通过优化这些隐形探针的制造并转变为交钥匙设备，我们将评估该平台作为 ASD 诊断和研究工具的可行性。然后，我们建议使用这一创新的可扩展分析平台来表征从 Phelan-McDermid 综合征患者的 iPS 细胞分化而来的神经元、突触和网络特征，然后评估新兴药物疗法使异常特征正常化的有效性。如果成功，我们的固态平台可以转变为高通量筛选设备，使研究人员能够重现 ASD 的早期发育阶段，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。

项目成果

Shank3 Is Part of a Zinc-Sensitive Signaling System That Regulates Excitatory Synaptic Strength.

Shank3 是调节兴奋性突触强度的锌敏感信号系统的一部分。

• 发表时间: 2016-08-31
• 作者: Arons, Magali H;Lee, Kevin;Thynne, Charlotte J;Kim, Sally A;Schob, Claudia;Kindler, Stefan;Montgomery, Johanna M;Garner, Craig C
• 通讯作者: Garner, Craig C