权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Photocleavable Mass-Tags for Spatial Multiomics of Alzheimer’s Brain Tissue

用于阿尔茨海默病脑组织空间多组学的光裂解质量标签

基本信息

批准号：
10684250
负责人：
Mark Lim
金额：
$ 108.1万
依托单位：
AMBERGEN, INC
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684250
关键词：
AD transgenic mice Address Aducanumab Affect Agar Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Amyloid beta-Protein Antibodies Autopsy Big Data Biological Markers Biotechnology Boston Brain Diseases Brain imaging Cholesterol Chronic Collaborations Data Analyses Dementia Diagnostic Drug Targeting Endosomes FDA approved Fluorescence Fourier transform ion cyclotron resonance Functional disorder Goals Health Care Costs Hospitals Human Image Image Analysis Imaging Techniques Imaging technology Immunohistochemistry Label Lectin Letters Link Lipids Machine Learning Malignant neoplasm of prostate Maps Methods Modeling Molecular Molecular Disease Molecular Target Monoclonal Antibodies Multiomic Data Mus Mutation Neurodegenerative Disorders Neurons Peptides Persons Pharmaceutical Preparations Pharmacologic Substance Phase Phospholipids Physics Polysaccharides Procedures Process Production Proteins Public Health Research Research Personnel Resolution Role Sampling Senile Plaques Source Spatial Distribution Specimen Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Tissue imaging Tissues Transgenic Mice Uncertainty Universities Validation Woman brain tissue cohort commercialization design drug candidate human disease human old age (65+)innovation instrument malignant breast neoplasm mass spectrometric imaging meter molecular imaging molecular pathology mouse model multiple omics novel operation peptide drug polypeptide presenilin-1 receptor small molecule tau Proteins

项目摘要

Summary/Abstract Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by progressively worsening dementia. AD currently affects over 6.2 million persons in the U.S. and approximately 30 million world-wide with 70% over the age of 65. The total public health cost of AD is expected to reach over $20 trillion by 2050. Despite extensive efforts to develop AD therapies including small molecules, monoclonal antibodies and peptide-based drugs, only aducanumab, whose efficacy is in doubt, has been approved by the FDA since 2004. A major challenge is elucidating the molecular pathology involved in AD in order to develop effective early diagnostics and drugs. While amyloid plaque formation due to aggregation of different Aβ-peptides has been an important focus, a myriad of other molecules including tau, neuronal and glial receptors, endosomal-lysosomal related proteins, glycans, phospholipids, cholesterol and metabolites have also been implicated in AD pathology. In order to obtain a detailed understanding of the possible role of these diverse molecular species as well as the molecular targeting of candidate drugs, there is an urgent need to develop sufficiently powerful, highly multiplexed and multiomic tissue imaging techniques that can map at cellular resolution the 2D-spatial distribution and association of these diverse, AD molecular players. The proposed Phase II project seeks to address this challenge by applying a new highly- multiplexed, targeted method termed mass spectrometric imaging immunohistochemistry (MSI-IHC™). MSI- IHC™ is based on the use of novel photocleavable mass-tags (PC-MTs) developed by AmberGen which when linked to antibody or lectin probes enable targeted biomolecules to be identified in the mass spectrometric image. This approach significantly exceeds the multiplex capability of fluorescence immunohistochemistry (IHC) and previous cleavable mass-tag based methods which are generally limited to 5 biomarkers or require extensive cycling procedures in the case of fluorescence. In addition, the ability to combine MSI-IHC™ with label-free, untargeted small molecule mass spectrometric imaging (MSI) as well as fluorescence IHC imaging, on the same sample, greatly extends its power. This is possible using unique double-labeled fluorescent-PC-MT probes and performing 2 rounds of MSI. Together, these innovations can provide a much more comprehensive multiomic picture of the role of various molecules in AD pathology. In Phase I, we have demonstrated the feasibility of this approach on mouse and human brain tissue specimens including the ability to image simultaneously a variety of AD related molecules. In Phase II we will build on this progress by applying MSI-IHC™ to human and transgenic AD mouse brain tissue obtained from collaborators and commercial sources. One goal, in collaboration with Prof. R.A. Nixon at NYU, a leading AD researcher, will be to investigate the role of neuronal endosomal dysfunction, the earliest known pathobiology specific to AD. Image analysis with be performed using novel statistical physics and AI methods previously developed for AD tissue and brain imaging.

摘要/文摘