Cell Specific Perturbations of the Proteome in Alzheimer's Disease

阿尔茨海默病中蛋白质组的细胞特异性扰动

基本信息

批准号：
10676828
负责人：
HOLLIS T. CLINE
金额：
$ 131.8万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2021-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676828
关键词：
Affect Affinity Chromatography Age Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model American Amino Acids Amyloid beta-Protein Precursor Animal Model Architecture Association Learning Astrocytes Biochemical Biotin Brain Brain region Cell Death Cell physiology Cells Charge Chemistry Chronic Complement Cre driver Data Defect Detection Development Disease Disease Progression Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Epigenetic Process Etiology Genes Genetic Transcription Genomics Glutamates Goals Hippocampus Image Impaired cognition Impairment Interneurons Knock-in Knowledge Label Learning Longitudinal Studies Mass Spectrum Analysis Measurement Measures Membrane Memory Memory Loss Messenger RNA Metabolism Methionine Methionine-tRNA Ligase Methods Microglia Molecular Monitor Mouse Protein Mus Nature Nerve Degeneration Nervous System Neurodegenerative Disorders Neuroglia Neurons Neurotransmitters Paint Pathway interactions Patients Pharmaceutical Preparations Physiological Population Post-Translational Protein Processing Principal Investigator Property Protein Biosynthesis Protein Dynamics Proteins Proteome Proteomics Recording of previous events Research Research Proposals Resources Rest Risk Factors Signal Transduction Structure Synapses Synaptic plasticity Testing Transfer RNA Translations aging brain amyloid peptide baby boomer bioinformatics pipeline brain cell cell type chemical genetics deep sequencing excitatory neuron experience extracellular familial Alzheimer disease frontal lobe genetic approach healthy aging human old age (65+)hyperphosphorylated tau in vivo inducible Cre inhibitory neuron insight member memory encoding memory retrieval mouse model mutant neural neural circuit neuroinflammation neuron loss normal aging novel novel marker optical imaging optogenetics protein degradation protein misfolding proteomic signature proteostasis tau Proteins tool virtual

项目摘要

Alzheimer’s disease (AD) is the leading cause of aging-related cognitive decline, affecting more than 5 million Americans over 65 years old, and the number of patients is expected to climb to 13 million as baby boomers age. Our ability to learn and remember declines with age due to progressive changes in synaptic connectivity and function. Synaptic abnormalities also commonly precede neuronal loss during early stages of Alzheimer’s disease (AD) and other neurodegenerative disorders. However, we are only beginning to understand the full spectrum of these abnormalities, their contributions to cognitive decline, and the underlying mechanisms. This challenge is largely attributed to the complexity of the brain and etiologies of aging and neurodegeneration. Hallmarks of advanced Alzheimer’s disease (AD) include accumulations of extracellular amyloid peptides and intracellular hyperphosphorylated tau protein as well as chronic neuroinflammation. While genes for familial AD have been identified, which shed substantial light on the etiology of the disease, the mechanisms behind sporadic onset AD still remain a mystery. While studies of transcriptional dynamics in the brain have been transformative, transcriptional dynamics do not correlate well with protein dynamics because protein synthesis, turnover and subcellular localization are more tightly regulated spatially and temporally than transcription. Studies have suggested that proteostasis declines with age, impairing cells from managing the inevitable misfolding of proteins. Our team will study protein dynamics in animal models based on bio-orthogonal non-canonical amino acid (BONCAT) protein labeling. These methods allow us to measure dynamics in protein synthesis and degradation in specific brain cell types relevant to AD. These measurements will provide new information about the disruption of normal cellular processes. The overreaching goal of our collaborative proposal is to bridge critical gaps in knowledge by leveraging the state-of-the-art methods for bio-orthogonal non-canonical amino acid tagging (BONCAT) and quantitative mass spectrometry (MS) to identify brain cell-type contributions to synaptic and neuronal decline associated with AD.

阿尔茨海默病 (AD) 是导致与衰老相关的认知能力下降的主要原因，影响着超过 500 万 65 岁以上的美国人，随着婴儿潮一代学习和记忆能力的老化，患者数量预计将攀升至 1300 万。在阿尔茨海默病（AD）和其他神经退行性疾病的早期阶段，由于突触连接和功能的逐渐变化，神经元的功能逐渐减弱，但我们才刚刚开始了解这些疾病的全部情况。这一挑战主要归因于大脑的复杂性以及衰老和神经变性的病因，晚期阿尔茨海默病 (AD) 的标志包括细胞外淀粉样肽和细胞内过度磷酸化 tau 蛋白的积累。虽然家族性 AD 的基因已被确定，这为该疾病的病因学提供了重要线索，但散发性 AD 背后的机制仍然是一个谜。虽然大脑转录动力学的研究具有变革性，但转录动力学与蛋白质动力学并没有很好的相关性，因为蛋白质合成、周转和亚细胞定位在空间和时间上比转录受到更严格的调控。研究表明，蛋白质稳态随着年龄的增长而下降，从而损害细胞。我们的团队将基于生物正交非规范氨基酸 (BONCAT) 蛋白质标记来研究动物模型中的蛋白质动力学，这些方法使我们能够测量蛋白质合成的动力学。这些测量将提供有关正常细胞过程破坏的新信息，我们合作提案的首要目标是通过利用最先进的方法来弥合知识方面的关键差距。用于生物正交非规范氨基酸标记 (BONCAT) 和定量质谱 (MS)，以确定脑细胞类型对 AD 相关突触和神经元衰退的贡献。