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.

项目总结： 神经原纤维缠结是阿尔茨海默病(AD)的一个标志，它是在tau从 微管和错位定位于受影响神经元的体树突间。病理性的tau是 然后从受影响的神经元中释放出来，跨突触传播，最终导致细胞死亡。 防止细胞内tau在躯体树突间的最初错误定位提出了一种 早期治疗目标，并可能导致限制AD进展的策略。XONA微流体公司 (“Xona”)建议开发一种可靠的、可重复的和可扩展的筛查方法来识别和验证 防止细胞内tau早期错误定位的治疗靶点。该项目的目标是建立 为AD和AD相关疾病提供临床前筛查服务的可行性。 初步数据表明，tau的本地化错误可以在Xona的专有划分中建模 限制β诱导的神经炎性介质暴露到轴突间室的微流控芯片。 由此导致的tau错误定位与突触小泡释放的增加有关，这是一致的。 与AD的病理生理学有关。Xona建议在此初步数据的基础上开发此屏幕，并使用 3D培养的人诱导多能干细胞分化神经元，更接近人类 疾病表型比小鼠模型。目标1将确定3D文化改进的程度 使用我们划分的芯片中的这些神经元，突触在2D培养中成熟。目标2将 用A-β诱导的神经炎性介质建立tau错误定位分析。此外，我们将评估 使用已建立的筛选潜力指标，该方法用于药物筛选的可靠性和适宜性。 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 可以筛选的化合物的数量。