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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/摘要阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征是病情逐渐恶化失智。目前，美国有超过 620 万人受到 AD 的影响，全球约有 3000 万人受到 AD 的影响。 70% 的人年龄在 65 岁以上。到 2050 年，AD 的公共卫生总成本预计将超过 20 万亿美元。广泛努力开发 AD 疗法，包括小分子、单克隆抗体和基于肽的自2004年以来，FDA批准的药物中，只有疗效存疑的aducanumab。一个重大挑战正在阐明 AD 所涉及的分子病理学，以便开发有效的早期诊断方法和药物。虽然不同 Aβ 肽聚集导致的淀粉样斑块形成一直是一个重要的焦点，但其他分子，包括 tau、神经元和神经胶质受体、内体溶酶体相关蛋白、聚糖、磷脂、胆固醇和代谢物也与 AD 病理有关。为了获得详细的了解这些不同分子种类的可能作用以及候选分子的分子靶向药物，迫切需要开发足够强大、高度多重和多组学的组织成像可以以细胞分辨率绘制这些不同 AD 的二维空间分布和关联的技术分子玩家。拟议的第二阶段项目旨在通过应用新的高度多重靶向方法称为质谱成像免疫组织化学 (MSI-IHC™)。 MSI- IHC™ 基于 AmberGen 开发的新型光裂解质量标签 (PC-MT) 的使用，当连接时抗体或凝集素探针能够在质谱图像中识别目标生物分子。这方法显着超过了荧光免疫组织化学 (IHC) 和之前的多重检测能力基于可切割质量标签的方法通常仅限于 5 个生物标志物或需要大量循环荧光情况下的程序。此外，能够将 MSI-IHC™ 与无标记、非靶向相结合小分子质谱成像 (MSI) 以及荧光 IHC 成像，在同一样品上，大大提高了扩大其权力。这可以使用独特的双标记荧光 PC-MT 探针并进行 2 轮 MSI 的。总之，这些创新可以提供更全面的多组学图景 AD 病理学中的各种分子。在第一阶段，我们已经证明了这种方法在小鼠和人脑组织标本包括同时对多种 AD 相关分子进行成像的能力。在第二阶段，我们将在此基础上再接再厉，将 MSI-IHC™ 应用于人类和转基因 AD 小鼠脑组织从合作者和商业来源获得。与 R.A. 教授合作的一个目标尼克松在纽约大学领先的 AD 研究人员将研究神经元内体功能障碍的作用，这是已知的最早的 AD 特有的病理生物学。使用新颖的统计物理和人工智能方法进行图像分析之前开发用于 AD 组织和脑成像。