Chaperome networks in Alzheimer's disease

阿尔茨海默病中的伴侣网络

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

抽象的拟议项目的目的是解决淀粉样蛋白β和Tau低聚的神经元应力如何触发物种诱导蛋白质连通性功能障碍，并改变蛋白质到神经元电路至器官水平的功能。我们专注于阿尔茨海默氏病（AD）中的合成功能障碍和认知缺陷。我们的研究背后的假设是，进入后，由淀粉样蛋白β触发的分子应激和 tau低聚物种在连通性中引起不良适应性的重新布线，进而引起大型子集的功能通过称为病理伴侣脚手架的下游神经元蛋白及其网络的伴侣。 Chisis实验室获得的初步数据证明了这一假设神经元谱系尤其容易在压力源之后形成表周伴，并且最容易受到影响表演体是蛋白质途径，在突触可塑性中具有关键作用。其他初步实验 Arancio实验室和其他人的研究提供了支持我们实验计划的可行性证明A和Tau低聚物会改变突触连通性，从而导致记忆丧失。我们的初步观察到将病理性伴侣结构拆除为正常的，折叠伴侣的重新平衡蛋白质网络的连通性和与身体条件下看到的蛋白质网络连接性也支持我们科学前提。为了执行这些研究，我们使用IPSC衍生的细胞模型和AD的鼠标模型，然后结合 Drs的协同专业知识。 Arancio（突触可塑性，AD的生物学），省（病理学化学生物学）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（HIPSC和基于AD的突触功能研究的基于基于的细胞模型的顾问）。我们预计我们的研究将提供全蛋白质组的功能见解和全面的机械性了解A和Tau低聚物如何导致突触失败和认知缺陷。此外为了提供有关AD生物学的新见解，我们的研究具有立即的翻译应用。与 Chisis Lab发现的Epichoperome疗法进入AD中的2阶段临床评估，在本提案中检验的假设可能会立即对人类AD产生影响。