Selective interactome vulnerability across the Alzheimer’s disease spectrum

阿尔茨海默病谱系中的选择性相互作用组脆弱性

基本信息

批准号：
10746269
负责人：
GABRIELA CHIOSIS
金额：
$ 116.55万
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：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746269
关键词：
Affinity Chromatography Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Autopsy Binding Biochemical Bioinformatics Biological Biology Brain Brain region Cell Communication Cell Cycle Cell model Cell physiology Cells Cellular biology Cerebellum Clinical Communities Complement Complex Data Data Analytics Data Set Defect Deposition Development Diagnostic Disease Disease Progression Elements Environmental Risk Factor Event Exposure to Functional disorder Funding Gender Genetic Genetic Predisposition to Disease Heat-Shock Proteins 90 Hippocampus Impaired cognition Individual Induced pluripotent stem cell derived neurons Inflammation Investigation Link Maps Mass Spectrum Analysis Measures Mediating Metabolism Methods Mining Modification Molecular Biology Molecular Chaperones Molecular Conformation Multiprotein Complexes Nature Neurodegenerative Disorders Neuroglia Neurons Outcome Output Pathologic Pathway interactions Patients Phenotype Post Translational Modification Analysis Post-Translational Protein Processing Process Proteins Proteome Site Specificity Stress Structure Synaptic plasticity System Testing Therapeutic Transgenic Mice Translations Validation axon guidance brain cell brain circuitry brain tissue conformer connectome crosslink effective therapy frontal lobe innovation insight interest member multidisciplinary network dysfunction novel protein protein interaction proteotoxicity scaffold spatiotemporal stressor structural determinants therapeutic development

项目摘要

ABSTRACT Mechanisms underlying selective vulnerability from cells to networks across the Alzheimer's disease (AD) spectrum remain unknown, limiting our understanding of disease and hampering development of effective therapies. We propose to identify protein-protein interaction (PPI) network dysfunctions in brain cells and regions as a gateway to selective vulnerability mechanisms in AD. To gain systems level insights, we propose to leverage our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and to employ a novel `omics platform called epichaperomics that provides direct information on PPI network changes. Preliminary studies indicate epichaperomes change how thousands of proteins interact and negatively impact PPI networks important for neuronal function, including synaptic plasticity, cell-to-cell communication, protein translation, cell cycle re-entry, axon guidance, metabolic processes and inflammation, leading to cell and connectome-wide dysfunction and cognitive decline. Parallel studies in transgenic mice and iPSC-derived neurons demonstrate epichaperome formation is a key event that negatively impacts cellular function, from early prodromal disease stages and throughout disease progression. Preliminary results in transgenic mice and postmortem AD brains suggest epichaperome formation occurs principally within vulnerable brain cells and regions. Accordingly, we hypothesize epichaperome formation, and in turn of epichaperome-mediated PPI network imbalances, over decades, not only results in defects within intrinsic neuronal proteins and protein pathways but also intercellularly, where it disrupts intrinsic network connectivity of cells and of brain circuits. We posit vulnerable neurons and brain regions have a higher propensity to accumulate epichaperomes, and epichaperome-mediated dysfunctions. In accordance with NOT-AG-21-040, we propose to uncover mechanisms of PPI dysfunctions within individual brain cells and regions as a portal into selective vulnerability in AD, which remains unknown and a key missing piece. We aim to i) investigate mechanisms that enable (i.e., epichaperomes, Aim 1) and ii) those that execute (i.e., impacted proteins and protein pathways, Aim 2) context-specific dysfunctions in PPI networks. As a key element in linking stressors-to- phenotype, we aim to uncover cell- and region-specific vulnerabilities within PPI networks induced by individual stressors (Aim 3). Results provide first-of-a-kind insights into the spatio-temporal formation and distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic, and genetic vulnerabilities. Outcomes are critical proteome-wide insights into interactome vulnerabilities, both on the nature and trajectory within vulnerable brain cells and brain regions. Raw datasets and data analytics will be deposited directly into free access sites for mining and hypothesis testing by members of the scientific community. In addition to defining technically challenging mechanistic insights into selective AD vulnerabilities, innovation includes diagnostics and therapeutics, as epichaperome-mediated dysfunctions are both imageable and targetable.

抽象的从细胞到整个阿尔茨海默氏病（AD）的选择性脆弱性的机制频谱仍然未知，限制了我们对疾病的理解并阻碍了有效的发展疗法。我们建议识别脑细胞和区域中蛋白质 - 蛋白质相互作用（PPI）网络功能障碍作为AD中选择性脆弱性机制的门户。为了获得系统级别的见解，我们建议利用我们在压力生物学中的发现，将相互作用网络扰动与长寿的形成联系起来寡聚脚手架称为表面伴侣，并采用一种新颖提供有关PPI网络更改的直接信息。初步研究表明表面伴侣改变了成千上万的蛋白质相互作用并对PPI网络产生负面影响，对神经元功能很重要，包括突触可塑性，细胞到细胞通信，蛋白质翻译，细胞周期重新进入，轴突指导，代谢过程和炎症，导致细胞和连接范围的功能障碍和认知能力下降。平行线在转基因小鼠和IPSC衍生的神经元中的研究表明，伴侣形成是一个关键事件，是从早期前序疾病阶段和整个疾病进展中对细胞功能产生负面影响。转基因小鼠和验尸广告大脑的初步结果表明，发生了伴侣的形成主要在脆弱的脑细胞和区域内。因此，我们假设伴侣形成，并在经过大数十年以来固有的神经元蛋白和蛋白质途径，但也会在其中破坏固有网络细胞和脑电路的连通性。我们认为脆弱的神经元和大脑区域具有更高的倾向积累表育体和表面伴侣介导的功能障碍。根据NOT-AG-21-040，我们建议发现单个脑细胞和区域内的PPI功能障碍的机制，作为门户 AD中的选择性脆弱性，这仍然是未知的，并且是关键缺失的作品。我们的目标是）调查能够启用（即表面伴侣，目标1）的机制和II）执行的机制（即受影响的蛋白质和蛋白质途径，目标2）PPI网络中的上下文特异性功能障碍。作为将压力源与 - 表型，我们旨在发现个人引起的PPI网络中细胞和区域特异性漏洞压力源（目标3）。结果提供了对时空形成和分布的首个见解整个AD光谱的附表及其与临床，病理和遗传脆弱性的关系。结果是对互动组漏洞的关键蛋白质组范围的洞察力，无论是关于性质还是轨迹在脆弱的脑细胞和大脑区域内。 RAW数据集和数据分析将直接存入科学界成员的开采和假设检验的免费访问站点。除了定义对选择性广告漏洞的技术具有挑战性的机械洞察力，创新包括诊断和治疗剂，因为伴随伴侣介导的功能障碍既可以想象又可定位。