High-Throughput 3D Multiscale Mass Spectrometry Imaging for Understanding Neurochemical Heterogeneity in Alzheimer's Disease

项目摘要： 了解阿尔茨海默病(AD)并确定有效的干预措施是最重要的 激动人心的科学前沿和最关键的医疗保健挑战。虽然几个人的角色 阿尔茨海默病的病理特征已被广泛研究，与 这些特征及其导致进行性神经元丢失和神经元脆弱性的机制 人们对广告的理解还不够充分。神经发生，海马体结构的一个独特特征，有 已被证明在衰老和阿尔茨海默病进展中起重要作用。年内出现异常的早期下降 在人类和动物模型中都观察到了阿尔茨海默病大脑中的神经发生，但分子 与不同神经发生相关的脆弱脑回路和神经元的变化概况 没有记录在案。傅里叶变换质谱仪(MSI)和单细胞分析 允许绘制和分析生物样本中成百上千个分子和单个 细胞，提供无与伦比的与AD相关的化学见解，如上所述。然而，有几个 存在主要挑战：(1)有限的吞吐量限制了对许多组织切片和 (2)与生物分子的高分辨率体积重建相关的挑战 跨样品和试验组的区域分析的分布；(3)需要整合 多尺度组织MSI和单细胞MS数据将细胞神经化学与组织化学联系起来 异质性。拟议的研究通过开发一套新的质量来解决这些挑战 基于光谱的技术，并使用这些技术来定位与AD相关的生物分子和 神经发生。Aim 1开发了一种新技术，通过以下方式显著提高FT-MSI的吞吐量 协同压缩感知和深度学习，以及集成多个MSI的多模式方法 AD和野生型小鼠脑的3D化学图谱切片。目标2开发了一种实验 用于生成多尺度组织MSI和单细胞MS数据的框架，用于 联合分析这些数据，以及基于组学的分子文库，以帮助解释MSI和Single 单元格数据。AIM 3利用在AIMS 1和2中开发的工具来确定时间和空间 阿尔茨海默病FAD小鼠模型中易受攻击的电路和神经元的特征。AIM 4调查了 海马神经发生对神经元易损性和AD进展的影响 多尺度MSI技术，以及创建小鼠大脑的3D化学图谱。建议数 研究，与技术和假设驱动的目标相结合，将扩大技术 MSI的包络，并转换如何生成和分析高分辨率MSI数据。建议数 测量将解决关于神经元脆弱性潜在机制的关键知识空白 在AD中，潜在地识别新的生物标记物和治疗靶点。

PROJECT ABSTRACT: Understanding Alzheimer’s disease (AD) and identifying effective interventions are among the most exciting scientific frontiers and most critical healthcare challenges. While the roles of several pathological hallmarks of AD have been extensively studied, the biochemical alterations associated with these hallmarks and the mechanisms underlying progressive neuron loss and neuronal vulnerability in AD are not fully understood. Neurogenesis, a unique characteristic of the hippocampal formation, has been shown to play important roles in aging and AD progression. Abnormal early declines in neurogenesis have been observed in AD brains in both human and animal models, but the molecular profile of alterations in vulnerable brain circuits and neurons associated with varied neurogenesis have not been documented. Fourier transform mass spectrometry imaging (MSI) and single cell analyses allow for mapping and profiling hundreds to thousands of molecules in biological samples and single cells, providing unparalleled chemical insights relevant to AD as discussed above. However, several major challenges exist: (1) the limited throughput that prohibits the analysis of many tissue slices and samples; (2) the challenges associated with high-resolution volumetric reconstruction of biomolecular distributions for regional analysis across samples and experimental groups; (3) the need for integrating multiscale tissue MSI and single-cell MS data to relate cellular neurochemistry to tissue chemical heterogeneity. The proposed research addresses these challenges by developing a suite of novel mass spectrometry-based technologies and uses these technologies to map biomolecules related to AD and neurogenesis. Aim 1 develops a new technology to significantly enhances the throughput of FT-MSI by synergizing compressed sensing and deep learning, and a multimodal approach to integrate many MSI slices for 3D chemical atlases of AD and wild type mouse brain. Aim 2 develops an experimental framework to generate multiscale tissue MSI and single-cell MS data, a computational framework to jointly analyze these data, and -omics based molecular libraries to aid in interpreting the MSI and single cell data. Aim 3 leverages the tools developed in Aims 1 & 2 to determine the temporal and spatial signature of vulnerable circuits and neurons in a FAD mouse model of AD. Aim 4 investigates the effects of hippocampal neurogenesis on neuronal vulnerability and AD progression using the new multiscale MSI technology, as well as creates 3D chemical atlas of the mouse brain. The proposed research, synergistic with both technology- and hypothesis- driven aims, will expand the technological envelop of MSI and transform how high-resolution MSI data are generated and analyzed. The proposed measurements will address critical knowledge gaps on the mechanism underlying neuronal vulnerability in AD, potentially identifying new biomarkers and therapeutic targets.