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

• 批准号: 10386016
• 负责人: GABRIELA CHIOSIS
• 金额: $ 116.25万
• 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: 2021-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386016
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anatomy; Autopsy; Autoradiography; Biochemical; Biochemistry; Bioinformatics; Biological Models; Biology; Biometry; Brain; Brain region; Cell Communication; Cell Cycle; Cell physiology; Cells; Cerebellum; Chemicals; Clinical; Clinical Research; Cognitive; Collaborations; Communities; Data; Data Analytics; Data Set; Defect; Dementia; Deposition; Diagnostic; Disease; Disease Progression; Event; Exposure to; Freezing; Functional disorder; Genetic Predisposition to Disease; Global Change; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Induced pluripotent stem cell derived neurons; Inflammation; Intervention; Knowledge Portal; Link; Mass Spectrum Analysis; Measures; Mediating; Metabolism; Methodology; Mining; Modeling; Molecular; Nature; Neuroglia; Neurons; Online Systems; Organ; Outcome; Pathogenesis; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Positioning Attribute; Positron-Emission Tomography; Preventive; Process; Proteins; Proteome; Proteomics; Recording of previous events; Sampling; Sorting - Cell Movement; Stem Cell Research; Stress; Structure; Synaptic plasticity; System; Temporal Lobe; Testing; Therapeutic; Transgenic Mice; Translating; Translations; Vulnerable Populations; age related; axon guidance; base; brain cell; brain tissue; cell type; cognitive performance; computerized data processing; connectome; data visualization; design; effective therapy; frontal lobe; functional outcomes; induced pluripotent stem cell; innovation; insight; interest; laser capture microdissection; mild cognitive impairment; mouse model; multidisciplinary; neuropathology; novel; protein protein interaction; scaffold; skills; spatiotemporal; stressor; targeted imaging

ABSTRACT Our application proposes to identify interactome network vulnerabilities in brain regions and cell populations that are selectively dysregulated in Alzheimer's disease (AD). The goals are to discover across the AD spectrum the mechanisms underlying such selective vulnerability. To gain systems level insights into interactome dysfunctions, we propose to make use of our discoveries in stress biology linking interactome network perturbations to the formation of long-lived oligomeric scaffolds termed epichaperomes, and of a novel `omics platform called chaperomics that provides direct information on interactome network changes. Our preliminary studies show epichaperomes change how thousands of proteins interact and negatively impact interactome 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 network-wide dysfunction and cognitive decline. Studies in transgenic mice and iPSC-derived neurons position epichaperome formation as an event that negatively impacts cellular function, from early in the disease process and throughout disease progression. Studies in transgenic mice and AD patients suggest epichaperome formation within AD vulnerable brain regions. These studies enable us to hypothesize accumulation of epichaperomes, and in turn of epichaperome-mediated interactome 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 (e.g., hippocampus and regions of the default mode network) have a higher propensity to accumulate epichaperomes, and in turn epichaperome-mediated dysfunctions, due to their intrinsic anatomy and biochemistry. In line with PAR-19-070, we intend to test these hypotheses within clinically and neuropathologically well-characterized postmortem human brains. We aim to investigate the regional and temporal trajectory of epichaperome formation (Aim 1) and to determine the negative impact of epichaperome formation on brain regions selectively vulnerable in AD (Aim 2). We also plan to explore neural cell populations most affected by this newly recognized pathologic mechanism (Aim 3). Outcomes are first-of-a-kind insights into the spatio-temporal distribution of epichaperomes across the AD spectrum and their relationship to clinical, pathologic and genetic vulnerabilities. Outcomes are also proteome-wide insights into interactome networks' vulnerabilities and dysfunctions, both on their nature and trajectory in vulnerable brain regions. Raw datasets and data analytics from interactome network studies will be deposited into free-access portals for mining and hypothesis generating access by the scientific community. A web-based user-interface will be designed to facilitate data processing and visualization. In addition to defining technically challenging insights into interactome dysfunctions and vulnerabilities, innovation includes both diagnostics and therapeutics, as epichaperome-mediated vulnerabilities are both targetable and imageable.

摘要 我们的应用程序建议识别大脑区域和细胞群体中的互动组网络漏洞 在阿尔茨海默病(AD)中选择性地失调。我们的目标是发现整个AD领域的 这种选择性脆弱性背后的机制。要获得对Interactome的系统级洞察 功能障碍，我们建议利用我们在压力生物学中的发现将相互作用组网络联系起来 对称为表壳体的长寿命低聚支架和一种新的组学的形成的扰动 一个名为伴侣组学的平台，提供有关互动组网络变化的直接信息。我们的预赛 研究表明，表壳体改变了数千种蛋白质的相互作用方式，并对相互作用组产生负面影响 对神经元功能很重要的网络，包括突触可塑性、细胞间通讯、蛋白质 翻译、细胞周期重新进入、轴突引导、代谢过程和炎症，导致整个网络 功能障碍和认知能力下降。转基因小鼠和IPSC来源神经元定位于上壳体的研究 形成为一种对细胞功能产生负面影响的事件，从疾病过程的早期到整个过程 疾病的发展。对转基因小鼠和阿尔茨海默病患者的研究表明，在阿尔茨海默病中形成了外壳体 脆弱的大脑区域。这些研究使我们能够假设表壳体的积累，进而 几十年来，外种皮介导的相互作用组网络不平衡不仅导致内部缺陷 固有的神经元蛋白质和蛋白质通路，但也包括细胞间，在那里它扰乱了固有网络 细胞和大脑回路的连通性。我们假设脆弱的神经元和大脑区域(例如，海马体和 默认模式网络的区域)具有更高的累积上壳体的倾向，进而 外种皮介导的功能障碍，由于其内在的解剖学和生物化学。符合PAR-19-070标准， 我们打算在临床和神经病理学特征良好的尸检中检验这些假说。 人类的大脑。我们的目标是研究外种皮形成的区域和时间轨迹(目标1) 并确定外种皮形成对阿尔茨海默病患者选择性易感脑区的负面影响 (目标2)。我们还计划探索受这种新发现的病理影响最大的神经细胞群。 机制(目标3)。结果是对上壳体时空分布的首次洞察 以及它们与临床、病理和遗传易损性的关系。结果是 也是对相互作用组网络的脆弱性和功能障碍的蛋白质组范围的洞察，既关于它们的性质，也关于它们 脑部脆弱区域的轨迹。来自互动组网络研究的原始数据集和数据分析将是 存放在免费访问门户中，供科学界进行挖掘和生成假设访问。一个 将设计基于网络的用户界面，以促进数据处理和可视化。除了定义 对互动体功能障碍和漏洞的技术见解具有挑战性，创新包括这两方面 诊断和治疗，因为外种皮介导的脆弱性既是有针对性的，也是可以成像的。