Chaperome networks in Alzheimer's disease

阿尔茨海默病中的伴侣网络

• 批准号: 10350644
• 负责人: OTTAVIO ARANCIO
• 金额: $ 119.95万
• 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/10350644
• 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; Disease; Exhibits; Exposure to; Functional disorder; Global Change; Goals; Heat-Shock Proteins 90; Hippocampus (Brain); 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; 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; base; 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 这项拟议项目的目标是解决淀粉样β蛋白和tau寡聚体如何触发神经元应激。 物种导致蛋白质连接功能障碍，并改变蛋白质-神经元-电路-器官水平的功能。 我们的重点是阿尔茨海默病(AD)的突触功能障碍和认知缺陷。 我们研究背后的假设是，一旦进入，淀粉样β蛋白和β-淀粉样蛋白引发的分子应力 Tau寡聚物种在连接性中诱导了不适应的重新布线，进而影响了大亚集的功能 下游神经元蛋白及其网络，通过病理分子伴侣支架 上壳体。这一假设得到了Chisis实验室获得的初步数据的支持，这些数据表明 神经细胞谱系特别容易在应激源后形成上壳体，并且最容易受到 上壳体是在突触可塑性中起关键作用的蛋白质通路。额外的初步实验 我们的实验计划的可行性由Arancio实验室和其他实验室的研究提供支持 证明A和tau寡聚体改变突触连接导致记忆丧失。我们的预赛 将病理性上壳体结构分解为正常、折叠的伴侣重新平衡的观察 在生理条件下看到的蛋白质网络的连通性和功能也支持我们的 科学前提。 为了进行这些研究，我们使用IPSC衍生的AD细胞模型和小鼠模型，并结合 Arancio博士(突触可塑性、AD生物学)、Chisis博士(病理化学生物学)的协同专业知识 蛋白质网络，翻译研究)，Fraser(AD和AD生物学的小鼠模型)，周(IPSC模型在 Merten(阿尔茨海默病)和Merten(AD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广泛的功能洞察和全面的、机械性的 了解A和tau寡聚体如何导致突触失败和认知缺陷。除了……之外 我们的研究提供了对AD生物学的新见解，立即具有翻译应用。带着一个 该病实验室发现的外种皮疗法正在进入AD的第二阶段临床评估， 在本提案中检验的假设可能对人类阿尔茨海默病产生直接影响。