The Phenotypic Landscape of Cognitive Decline as Revealed by Next-Generation Multiplexed Ion Beam Imaging

下一代多重离子束成像揭示认知衰退的表型景观

• 批准号: 9910356
• 负责人: Robert michael Angelo
• 金额: $ 51.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910356
• 关键词: Abbreviations; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; American; Amyloid beta-Protein; Apolipoprotein E; Biology; Brain; Brain region; Cessation of life; Color; Communities; Data; Disasters; Disease; Electrons; Family; Financial compensation; Fluorescence-Activated Cell Sorting; Formalin; Foundations; Funding; Gene Proteins; Generations; Genetic Predisposition to Disease; Genetic Risk; Genomics; Genotype; Goals; Healthcare Systems; Hippocampus (Brain); Human; Image; Image Analysis; Immune system; Immunohistochemistry; Impaired cognition; Infrastructure; Laboratories; Late Onset Alzheimer Disease; Longitudinal cohort; Malignant Neoplasms; Measurement; Middle frontal gyrus structure; Molecular; Multiplexed Ion Beam Imaging; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Paraffin Embedding; Participant; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Population; Proteins; Public Health; Research; Resistance; Resolution; Resources; Role; Running; Scientist; Senile Plaques; Signal Transduction; Spectrometry, Mass, Secondary Ion; Surface; Synapses; Technology; Testing; Time; Translating; Work; aged; aging brain; area striata; burden of illness; collaborative approach; computational pipelines; data sharing; data warehouse; disability; gene product; high dimensionality; imaging modality; imaging platform; imaging study; innovation; insight; instrumentation; machine learning method; mental state; molecular imaging; molecular phenotype; multiplexed imaging; neuroinflammation; neuropathology; new therapeutic target; next generation; novel; paired helical filament; pre-clinical; predictive signature; repository; risk variant; statistical and machine learning; symposium; web portal

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a leading cause of disability and death in the US and a major global public health problem. Time is running short if we wish to avert a global public health disaster with untold suffering, disruption of families, and severe challenges to health care systems and economies. Solutions will come only from innovative research. Genomic studies for late-onset AD (LOAD) have identified over 20 risk loci; however, translating the relevant molecules identified by genomics to AD-specific mechanistic pathways has been challenging. Our application, entitled “The Phenotypic Landscape of Cognitive Decline Revealed by Next- Generation Multiplexed Ion Beam Imaging,” is highly responsive to this urgent scientific need by proposing a uniquely innovative molecular imaging platform called multiplexed ion beam imaging (MIBI) that will determine high dimensional protein interactions for AD-relevant molecules identified by genomics studies in normal and pathological states. Our proposal has three Specific Aims. In Aim 1, we propose to analyze four regions in healthy aged brains: two sectors of the hippocampal pyramidal layer and from two isocortical regions. Next- generation MIBI instrumentation will be used to image simultaneously 30+ proteins that mark subtypes of neurons, synapses, and non-neuronal cells, while covering regulatory signaling, neuro-inflammatory components, and AD risk gene protein products with subcellular resolution. In Aim 2, we propose to use the same multiplexed imaging methods in AD brain stratified by APOE genotype. We will analyze these data with statistical machine learning methods already established in our laboratory, similar to what we have done previously with different cancers and the immune system. In Aim 3, using infrastructure we have already have established, we will create a web-based portal where all of the images from this study can be accessed, multi- color overlays generated ad hoc, and all the features we derive shared freely. We propose a transformative, collaborative approach to AD that leverages a long-standing NIA-funded longitudinal cohort and is highly responsive to the National Alzheimer's Plan. These novel insights will illuminate pathways that hold potential for new therapeutic targets and will create a shared research resource and analysis platform for the community of scientists committed to developing solutions for AD.

项目摘要/摘要 阿尔茨海默氏病（AD）是美国残疾和死亡的主要原因，也是全球主要的公共卫生 问题。如果我们想避免遭受不为人知的痛苦，时间很短， 家庭的破坏，以及对医疗保健系统和经济的严重挑战。解决方案只会出现 来自创新研究。晚发广告（负载）的基因组研究已确定20多个风险基因座；然而， 将基因组学鉴定的相关分子转换为AD特异性机械途径已经是 具有挑战性的。我们的应用名为“接下来的认知下降的表型景观 生成多路复用的离子光束成像”，通过提出一个对这种紧急科学需求的反应 称为多路复用离子束成像（MIBI）的独特创新分子成像平台，该平台将决定 通过基因组研究在正常和 病理状态。我们的建议具有三个具体目标。在AIM 1中，我们建议分析四个区域 健康老化的大脑：海马锥体层的两个部门和两个等皮质区域。下一个- MIBI仪器的一代将用于图像30多个标记亚型的蛋白质 神经元，突触和非神经元细胞，同时涵盖调节信号，神经炎症 组件和具有亚细胞分辨率的AD风险基因蛋白产物。在AIM 2中，我们建议使用 通过APOE基因型分层的AD脑中的相同多重成像方法。我们将使用 我们的实验室已经建立的统计机器学习方法，类似于我们所做的 以前有不同的癌症和免疫系统。在AIM 3中，使用基础架构我们已经拥有 成立，我们将创建一个基于Web的门户 彩色叠加层产生了临时，以及我们自由共享的所有功能。我们提出了一个变革性的， 协作方法来利用长期以来的NIA资助的纵向队列，并且非常高 响应国家阿尔茨海默氏症的计划。这些新颖的见解将阐明具有潜力的途径 对于新的治疗目标，将为社区创建共享的研究资源和分析平台 致力于开发AD解决方案的科学家。