Chaperome networks in Alzheimer's disease

阿尔茨海默病中的伴侣网络

• 批准号: 10613466
• 负责人: OTTAVIO ARANCIO
• 金额: $ 118.32万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613466
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Biology; Brain; Cell model; Cells; Chemicals; Chronic; Cognition; Cognitive deficits; Communication; Complex; Data; Defect; Deterioration; Disease; Equilibrium; Exhibits; Exposure to; Functional disorder; Global Change; Goals; Heat-Shock Proteins 90; Hippocampus; Human; Image; Impairment; In Vitro; Individual; Investigation; Kinetics; Knock-in Mouse; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Link; Long-Term Potentiation; Mediating; Memorial Sloan-Kettering Cancer Center; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Molecular Chaperones; Mus; Mutation; Nature; Neurons; Non-Invasive Detection; Organ; Outcome; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Physiological; Proteins; Proteome; Publishing; Role; Set protein; Stem Cell Research; Stress; Structure; Swedish mutation; Synapses; Synaptic plasticity; Testing; Therapeutic; Translational Research; Validation; Work; abeta oligomer; age related; clinically relevant; cognitive function; experimental study; flexibility; in vivo; induced pluripotent stem cell; insight; mouse model; neuronal circuitry; protein folding; protein protein interaction; proteostasis; research clinical testing; response; scaffold; small molecule; stressor; synaptic failure; synaptic function; tau Proteins; tau aggregation; tau expression; translational applications

ABSTRACT The goal of the proposed project is to address how neuronal stress triggered by amyloid-beta and tau oligomeric species induces protein connectivity dysfunctions and alters protein-to-neuronal circuit-to-organ level function. Our focus in on synaptic dysfunction and cognitive deficits in Alzheimer's disease (AD). The hypothesis behind our investigation is that upon entry, the molecular stress triggered by amyloid-beta and tau oligomeric species induces a maladaptive rewiring in the connectivity, and in turn the function of large subsets of downstream neuronal proteins and their networks, through pathologic chaperome scaffolds termed epichaperomes. This hypothesis is supported by preliminary data obtained by the Chiosis lab showing that neuronal lineages are especially prone to form epichaperomes following stressors, and that most vulnerable to epichaperomes are protein pathways with key roles in synaptic plasticity. Additional preliminary experiments supporting feasibility of our experimental plan are provided by studies from the Arancio laboratory and others demonstrating that A and tau oligomers alter synaptic connectivity leading to memory loss. Our preliminary observation that dismantling the pathologic epichaperome structures into normal, folding chaperones rebalances protein network connectivity and functionality to those seen in physiological conditions, are also in support of our scientific premise. To execute these studies, we use iPSC-derived cellular models and mouse models of AD and combine the synergistic expertise of Drs. Arancio (synaptic plasticity, biology of AD), Chiosis (chemical biology of pathologic protein networks, translational research), Fraser (mouse models of AD and AD biology), Zhou (iPSC models in disease) and Mertens (consultant on hiPSC and iN-based cellular models for synaptic function study in AD). We expect that our studies will deliver proteome-wide functional insights and comprehensive, mechanistic understanding into how A and tau oligomers lead to synaptic failure and cognitive defects. In addition to providing new insights into AD biology, our studies have immediate translational applications. With an epichaperome therapeutic discovered by the Chiosis lab moving into Phase 2 clinical evaluation in AD, hypotheses tested within the present proposal may have immediate impact in human AD.

摘要 该项目的目标是解决β淀粉样蛋白和tau寡聚体如何引发神经元应激 物种诱导蛋白质连接功能障碍并改变蛋白质-神经元回路-器官水平功能。 我们专注于阿尔茨海默病（AD）的突触功能障碍和认知缺陷。 我们研究背后的假设是，在进入时，由淀粉样蛋白β和 tau寡聚物种类诱导连接中的适应不良的重新布线，并且反过来诱导大子集的功能 下游神经元蛋白及其网络，通过病理伴侣蛋白支架，称为 epichaperomes。这一假设得到了Chiosis实验室获得的初步数据的支持，这些数据显示， 神经元谱系特别容易在应激源后形成epichaperomes，并且最容易受到 epichaperomes是在突触可塑性中具有关键作用的蛋白质通路。额外的初步实验 阿兰西奥实验室和其他机构的研究为我们的实验计划提供了支持 这表明A和tau寡聚体改变了突触连接性，导致记忆丧失。我们的初步 观察到将病理性epichaperome结构分解为正常的折叠分子伴侣重新平衡 蛋白质网络的连接性和功能性与生理条件下的蛋白质网络连接性和功能性相比，也支持我们的研究。 科学前提。 为了进行这些研究，我们使用iPSC衍生的细胞模型和AD的小鼠模型，并将联合收割机与细胞模型结合。 Arancio博士（突触可塑性，AD生物学），Chiosis（病理化学生物学） 蛋白质网络，翻译研究），弗雷泽（AD和AD生物学的小鼠模型），周（iPSC模型， 疾病）和Mertens（AD中突触功能研究的hiPSC和基于iN的细胞模型顾问）。 我们希望我们的研究将提供蛋白质组范围的功能见解和全面的， 了解A β和tau寡聚体如何导致突触失效和认知缺陷。除了 我们的研究为AD生物学提供了新的见解，具有直接的翻译应用。与 由Chiosis实验室发现的epichaperome治疗剂进入AD的2期临床评价， 在本建议中测试的假设可能对人类AD有直接影响。