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.

阿尔茨海默氏病（AD）是与衰老有关的认知能力下降的主要原因，影响了65岁以上的500万美国人，随着婴儿潮一代的年龄，预计患者的数量将增加到1300万。由于突触连通性和功能的逐步变化，我们学习和记住随着年龄的增长而记住的能力。在阿尔茨海默氏病（AD）和其他神经退行性疾病的早期阶段，突触异常也通常是在神经元丧失之前。但是，我们才开始了解这些异常的全部范围，它们对认知能力下降的贡献以及潜在的机制。这一挑战在很大程度上归因于大脑的复杂性和衰老和神经变性的病因。晚期阿尔茨海默氏病（AD）的标志包括细胞外淀粉样蛋白宠物和细胞内高磷酸化的tau蛋白以及慢性神经炎症的积累。虽然已经确定了家庭广告的基因，这对该疾病的病因揭示了大量阐明，但零星发作AD背后的机制仍然是一个谜。尽管大脑中转录动力学的研究是变换性的，但转录动力学与蛋白质动力学没有很好的相关性，因为蛋白质的合成，周转和亚细胞定位在空间和临时上比转录更紧密地调节。研究表明，随着年龄的增长，蛋白质量下降，从而损害了不可避免的蛋白质错误折叠的细胞。我们的团队将研究基于生物正交非传统氨基酸（Boncat）蛋白质标签的动物模型中的蛋白质动力学。这些方法使我们能够测量与AD相关的特定脑细胞类型中蛋白质合成和降解的动力学。这些测量结果将提供有关正常细胞过程中断的新信息。我们的协作提案的过度目标是通过利用生物 - 正交的非基本氨基酸标记（BONCAT）和定量质谱（MS）的最新方法来弥合知识的关键差距，并确定脑细胞细胞型对与AD相关的突触和神经元下降的贡献。