Tau mislocalization assay to screen AD therapeutics using compartmentalized chips

使用区室芯片筛选 AD 疗法的 Tau 错误定位测定

• 批准号: 10561610
• 负责人: ANNE MARION TAYLOR
• 金额: $ 26.66万
• 依托单位: XONA MICROFLUIDICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561610
• 关键词: 3-Dimensional; Acetaminophen; Adult; Affect; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Amyloid beta-Protein; Astrocytes; Axon; Biological Assay; Biological Models; Biology; Cell Death; Cell model; Cells; Data; Defect; Development; Disease; Disease Progression; Disease model; Dissociation; Drug Modelings; Drug Screening; Exposure to; Functional disorder; Future; Gene Expression Profiling; Goals; Hippocampus; Human; Hydrogels; Individual; Induced pluripotent stem cell derived neurons; Laboratories; Legal patent; Letters; Microfluidic Microchips; Microfluidics; Microglia; Microtubules; Modeling; Mus; Neurofibrillary Tangles; Neuronal Differentiation; Neurons; Neurosciences; Pathologic; Phase; Phenotype; Population; Positioning Attribute; Public Health; Rattus; Reproducibility; Research; Research Personnel; Running; Services; Speed; Synapses; Synaptic Vesicles; Technology; Testing; Tetrodotoxin; Therapeutic; Therapeutic Uses; Validation; Work; axon growth; cell injury; density; disease phenotype; drug use screening; human disease; human embryonic stem cell; human stem cells; immunocytochemistry; improved; induced pluripotent stem cell; interest; mouse model; neuroinflammation; pharmacologic; pre-clinical; prevent; response; scale up; screening; screening services; stem cell differentiation; tau Proteins; therapeutic target; three dimensional cell culture; tv watching; vesicular release

PROJECT SUMMARY: Neurofibrillary tangles, a hallmark of Alzheimer's disease (AD), are formed following tau dissociation from microtubules and mislocalization to the somatodendritic compartment of affected neurons. Pathological tau is then released from affected neurons and spreads trans-synaptically eventually leading to cell death. Preventing the initial mislocalization of intracellular tau within the somatodendritic compartment presents an early therapeutic target and may lead to strategies that limit the progression of AD. Xona Microfluidic, Inc. (“Xona”) proposes to develop a reliable, reproducible, and scalable screening assay to identify and validate therapeutic targets that prevent early mislocalization of intracellular tau. The goal of this project is to establish the feasibility of providing preclinical screening services using this assay for AD and AD-related diseases. Preliminary data suggests that tau mislocalization can be modeled in Xona's proprietary compartmentalized microfluidic chips by restricting exposure of Aβ-induced neuroinflammatory media to the axonal compartment. The resulting tau mislocalization correlates with an increase in synaptic vesicle release, which is consistent with AD pathophysiology. Xona proposes to develop this screen on the basis of this preliminary data and using human induced pluripotent stem cell differentiated neurons cultured in 3D, which more closely mimic human disease phenotypes than murine models. Aim 1 will determine the extent to which 3D cultures improve synapse maturation over 2D cultures using these neurons within our compartmentalized chips. Aim 2 will develop a tau mislocalization assay using Aβ-induced neuroinflammatory media. Further, we will evaluate the reliability and suitability of this assay for drug screening using an established metric of screening potential. Once feasibility is shown, Xona will focus on forming partnerships with potential customers and scaling up the number of compounds that can be screened.

项目摘要： 神经原纤维缠结是阿尔茨海默氏病（AD）的标志，在tau解离之后形成 微管和不定位到受影响神经元的体内室室。病理tau是 然后从受影响的神经元中释放，并传播跨突触最终导致细胞死亡。 防止在体内室内细胞内tau的初始错误定位为 早期的治疗靶标，并可能导致限制AD进展的策略。 Xona Microfluidic，Inc。 （“ XONA”）提出开发可靠，可重复和可扩展的筛选测定法以识别和验证的提案 预防细胞内TAU早期错误定位的治疗靶标。该项目的目的是建立 使用此测定法作为广告和广告相关疾病提供临床前筛查服务的可行性。 初步数据表明，可以在Xona专有的分区化中对TAU错误定位进行建模 微流体芯片通过限制Aβ诱导的神经炎性培养基暴露于轴突室。 由此产生的tau错误定位与突触囊泡释放的增加相关，这是一致的 具有AD病理生理学。 XONA提议根据此初步数据开发此屏幕并使用 人类诱导的多能干细胞分化的神经元在3D中培养，它们更亲密地模仿人 疾病表型比鼠模型。 AIM 1将确定3D文化改善的程度 使用这些神经元在我们的分室化芯片中使用这些神经元在2D培养物上的突触成熟。 AIM 2意志 使用Aβ诱导的神经炎症培养基开发TAU错误定位测定法。此外，我们将评估 使用已建立的筛选潜力的指标，该测定法对药物筛查的可靠性和适用性。 一旦显示出可行性，Xona将专注于与潜在客户建立合作伙伴关系并扩大规模 可以筛选的化合物数量。