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.

抽象的阿尔茨海默病（AD）从细胞到网络的选择性脆弱性的潜在机制谱仍然未知，限制了我们对疾病的了解并阻碍了有效治疗方法的开发疗法。我们建议识别脑细胞和区域中的蛋白质-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。为了获得系统级见解，我们建议利用我们在应激生物学方面的发现将相互作用组网络扰动与长寿的形成联系起来称为表壳组的寡聚支架，并采用称为表壳组的新型组学平台提供有关 PPI 网络变化的直接信息。初步研究表明表质体如何改变数以千计的蛋白质相互作用并对 PPI 网络产生负面影响，这些网络对神经元功能很重要，包括突触可塑性、细胞间通讯、蛋白质翻译、细胞周期重入、轴突引导、代谢过程和炎症，导致细胞和连接组范围的功能障碍和认知能力下降。平行线对转基因小鼠和 iPSC 衍生神经元的研究表明，外表面体形成是一个关键事件，从早期前驱疾病阶段到整个疾病进展，都会对细胞功能产生负面影响。转基因小鼠和死后 AD 大脑的初步结果表明发生了表层体形成主要在脆弱的脑细胞和区域内。因此，我们假设外表面体形成，并且几十年来，外表面介导的 PPI 网络失衡不仅导致内部缺陷内在神经元蛋白质和蛋白质通路，而且在细胞间，它破坏内在网络细胞和大脑回路的连接。我们假设脆弱的神经元和大脑区域有更高的倾向积累表质体和表质体介导的功能障碍。根据 NOT-AG-21-040，我们建议揭示个体脑细胞和区域内 PPI 功能障碍的机制，作为研究的门户 AD 中的选择性脆弱性仍然未知，并且是一个关键的缺失部分。我们的目标是 i) 调查使机制（即表壳体，目标 1）和 ii）执行机制（即受影响的蛋白质和蛋白质通路，目标 2) PPI 网络中特定环境的功能障碍。作为将压力源与表型，我们的目标是揭示 PPI 网络中由个体引起的细胞和区域特异性脆弱性压力源（目标 3）。结果为时空形成和分布提供了前所未有的见解 AD 谱系的表层体及其与临床、病理和遗传脆弱性的关系。结果是对相互作用组漏洞的关键蛋白质组洞察，包括性质和轨迹在脆弱的脑细胞和大脑区域内。原始数据集和数据分析将直接存入科学界成员可以免费访问网站进行挖掘和假设检验。除了定义对选择性 AD 漏洞进行技术上具有挑战性的机械洞察，创新包括诊断和治疗，因为表层介导的功能障碍既可成像又可靶向。