Elucidating Molecular Drivers of Aging and Alzheimer's Disease via Multimodal Imaging Mass Spectrometry

通过多模态成像质谱阐明衰老和阿尔茨海默病的分子驱动因素

基本信息

批准号：
10516633
负责人：
Rena A. S. Robinson
金额：
$ 76.27万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516633
关键词：
Academic Medical Centers Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Amyloid beta-Protein Analytical Chemistry Anterior Architecture Astrocytes Atlases Autophagosome Axon Biochemistry Biogenesis Biology Blood capillaries Brain Brain Mapping Cellular biology Cerebral Amyloid Angiopathy Cerebral hemisphere hemorrhage Cerebrum Clinical Complement Computer Analysis Computer Vision Systems Computers and Advanced Instrumentation Data Data Analyses Data Science Data Set Deposition Development Disease Disease Marker Environment Epidemic Eye Glean Gliosis Goals Heterogeneity Hippocampus (Brain)Histology Human Image Impaired cognition Infrastructure Investigational Therapies Kidney Laboratories Lesion Link Lipids Lobe Lysosomes Machine Learning Maps Mass Spectrum Analysis Membrane Methodological Studies Methodology Microglia Microscopy Modality Molecular Molecular Analysis Molecular Profiling Multimodal Imaging Multiomic Data Multivariate Analysis Neurites Neurofibrillary Tangles Neurology Neurons Neuropil Threads Organelles Pancreas Parietal Lobe Pathologic Pathology Pathway interactions Performance Process Proteins Proteome Proteomics Protocols documentation Research Research Personnel Resolution Resources Senile Plaques Source Spatial Distribution Superior temporal gyrus Systems Biology Technology Tissues Universities Validation Vascular Diseases Work arteriole base brain tissue cell type comparative disease heterogeneity disorder subtype effective therapy experience genetic architecture human tissue hyperphosphorylated tau imaging facilities imaging modality imaging platform improved innovation insight interest learning network lipidome lipidomics mass spectrometric imaging metabolome molecular imaging molecular marker mouse model multimodality multiple omics neuropathology normal aging novel therapeutic intervention older patient patient population supervised learning tool transcriptome transcriptomics

项目摘要

PROJECT SUMMARY: The overarching goal of the proposed work is to apply a platform of integrated multiomic imaging modalities and spatially resolved molecular characterization technologies to normal aging and Alzheimer’s disease brain tissues in order to discover and define key molecules and pathways that drive the underlying heterogeneity of the disease. This work will leverage the unique resources of the Mass Spectrometry Research Center and VU Biomolecular Imaging Center, as well as the world-class clinical environment of the Vanderbilt University Medical Center, and the advanced biocomputational infrastructure available through the data analysis laboratories at Vanderbilt University and the Delft University of Technology. The main objectives of our proposed work, which we believe will move the field forward, are to: (1) engage the molecular complexities of Alzheimer’s disease in a new and robust way to create molecular atlases of the heterogenous neuropathologies observed in human brain tissue, (2) define how the molecular underpinnings of neuritic plaques and neurofibrillary tangles overlap with pathways implicated in contributory neuropathologies to inform more precise development of experimental therapies; and (3) deploy multiomic tools to document cell-type specific molecular changes between normal aging and Alzheimer’s disease in well-defined microanatomical regions so changes in the metabolome, lipidome, proteome, and transcriptome can be attributed to the correct cell types and microenvironment. With this suite of technologies, advanced data analysis capabilities, and prior experience in developing atlases of healthy-for-age human tissues, this team will generate datasets with unprecedented detail and the potential to drive molecular discovery. To accomplish these aims, we assembled an interactive and established team of investigators, covering complementary expertise in Alzheimer’s disease, cell biology, analytical chemistry, and data science; and with direct in-house access to advanced instrumentation and facilities. We believe that our spatially resolved and molecularly comprehensive approach will lead to improved mechanistic understanding of Alzheimer’s disease and that these insights could inform better treatment options.

项目摘要：拟议工作的总体目标是应用一个集成的平台多构想成像方式和空间分辨的分子表征技术达到正常衰老和阿尔茨海默氏病脑组织，以发现和定义关键分子和推动疾病潜在异质性的途径。这项工作将利用独特的质谱研究中心和VU生物分子成像中心的资源也作为范德比尔特大学医学中心的世界一流临床环境，高级范德比尔特大学的数据分析实验室可用的生物计算基础设施和代尔夫特技术大学。我们提出的工作的主要目标，我们相信将向前移动该领域，为：（1）使阿尔茨海默氏病的分子复杂性参与创建在观察到异质神经病理学分子图谱的新方法人脑组织，（2）定义神经斑和神经原纤维的分子基础如何缠结与在贡献神经病理学中实施的途径重叠，以便更精确地告知实验疗法的发展；（3）部署多构想工具来记录特定于细胞类型的特定工具正常衰老和阿尔茨海默氏病之间的分子变化地区的代谢组，脂肪组，蛋白质组和转录组的变化可以归因于正确的细胞类型和微环境。使用这套技术，高级数据分析能力和事先在发展健康人类组织的地图集方面的经验，该团队将生成具有前所未有的细节的数据集，并具有推动分子发现的潜力。到完成这些目标，我们组建了一个互动和成熟的调查员团队，涵盖了在阿尔茨海默氏病，细胞生物学，分析化学和数据科学方面完全专业知识；并可以直接访问高级仪器和设施。我们相信我们的空间已解决和分子全面的方法将导致对机械理解的改善阿尔茨海默氏病，这些见解可以为更好的治疗选择提供信息。