Project 2: Particle and brain mapping of CSF proteins using elemental reporters with mass spectrometry

项目 2：使用元素报告仪和质谱法对 CSF 蛋白进行粒子和脑图谱分析

• 批准号: 10573262
• 负责人: Thomas J Montine
• 金额: $ 48.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573262
• 关键词: Abbreviations; Affinity; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-Protein; Apolipoproteins; Apoptotic; Biological; Biological Process; Brain; Brain Mapping; Brain region; Cells; Cellular Structures; Cellular biology; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clinical; Color; Communities; Corpus striatum structure; Cytometry; Data; Data Storage and Retrieval; Dementia with Lewy Bodies; Diagnostic; Disasters; Elements; Flow Cytometry; Formalin; Glutamates; Health; Human; Image; Individual; Infrastructure; Injury; Ions; Lewy Bodies; Lewy neurites; Lipoproteins; Maps; Mass Spectrum Analysis; Medical; Mitochondria; Monoclonal Antibodies; Multiplexed Ion Beam Imaging; Neurofibrillary Tangles; Neurons; Paraffin Embedding; Parkinson' s Dementia; Pathologic; Pathway interactions; Production; Proteins; Proteome; Proteomics; Public Health; Reagent; Reporter; Research; Resources; Role; Sampling; Scientist; Senile Plaques; Statistical Data Interpretation; Structure; Subcellular structure; Synapses; Testing; Therapeutic; alpha synuclein; collaborative approach; data dissemination; data sharing; exosome; extracellular vesicles; hippocampal pyramidal neuron; human imaging; imaging study; insight; interest; microvesicles; mild cognitive impairment; multiplexed imaging; nervous system disorder; neuropathology; next generation; particle; protein TDP-43; protein distribution; response to injury; symposium; tau aggregation; tissue resource; translational proteomics; web portal

Abstract Alzheimer's disease (AD) is a major threat to health of older individuals and is a looming public health disaster. Promised solutions in diagnostics and therapeutics will come only through research. Project 2 proposes to gain biological and medical insights into the proteins discovered in the Center by multiplex mapping to specific CSF extracellular vesicles (EV) and lipoproteins (LP), and to specific cells and subcellular structures in specific regions of brain. Proteins in CSF remain the best performing biomarkers for AD. CSF proteins exist in various forms: free in solution, on a unique class of LP, and on EV that include exosomes, microvesicles, and apoptotic bodies. LP and EV have varying mechanisms of production and biological functions. Localization and relative quantification of proteins of interest discovered in Project 1 to each class of CSF particles will provide powerful insight into cell of origin, cellular biology, and potential medical meaning. Further biological and medical insights can be gained by carefully mapping proteins in human brain. Indeed, the power of multiplexed imaging is its ability to reveal co-localization or mutual exclusivity, and to infer regulatory roles and gain mechanistic insight. For example, we think very differently about the biological roles of proteins restricted in their expression to synapses vs. mitochondria, glutamatergic vs. GABA-ergic neurons, or hippocampal pyramidal neurons vs. striatal medium spiny neurons. In pathologic states, co-localization with hallmark pathologic structures (major protein) highlights pathways of injury and response to injury: senile plaques (amyloid beta peptides), neurofibrillary degeneration (paired helical filament-tau), Lewy bodies and neurites (phospho-alpha-synuclein), and phospho-TDP-43 inclusions. We will test the hypothesis that multiplex analysis of CSF particles as well as subcellular, cellular, and regional mapping will provide key biological and medical insights into CSF proteins discovered by de novo proteomic analysis of CSF in Project 1. The same probes will be applied to CSF LP and EV using flow cytometry, and to brain regions using Multiplexed Ion Beam Imaging (MIBI).

摘要