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

项目摘要/摘要 阿尔茨海默病(AD)是美国导致残疾和死亡的主要原因，也是全球主要的公共卫生问题 有问题。如果我们希望避免一场痛苦不堪的全球公共卫生灾难，时间不多了， 家庭受到破坏，卫生保健系统和经济面临严峻挑战。只有解决方案才会出现 来自创新研究。迟发性AD(LOAD)的基因组研究已经确定了20多个危险基因；然而， 将基因组学确定的相关分子翻译成AD特有的机制途径 很有挑战性。我们的申请题为“NEXT揭示的认知衰退的表型景观-- 新一代多路离子束成像“是对这种迫切的科学需求的高度响应，提出了一种 独一无二的创新分子成像平台，称为多路离子束成像(MIBI)，将确定 基因组学研究确定AD相关分子的高维蛋白质相互作用 病态。我们的建议有三个具体目标。在目标1中，我们建议分析以下四个区域 健康的老年大脑：海马锥体层的两个扇区，来自两个等皮质区域。下一步- 新一代MIBI仪器将用于同时成像30多种标记亚型的蛋白质 神经元、突触和非神经元细胞，同时涵盖调节信号、神经炎性 成分，以及具有亚细胞分辨率的AD风险基因蛋白产品。在目标2中，我们建议使用 按APOE基因分层的AD脑内相同的多路成像方法。我们将对这些数据进行分析 我们实验室已经建立了统计机器学习方法，类似于我们所做的 以前与不同的癌症和免疫系统有关。在目标3中，使用我们已经拥有的基础设施 建立后，我们将创建一个基于Web的门户，在其中可以访问此研究的所有图像，多 颜色覆盖生成了特别的，所有我们派生的功能都免费共享。我们提出了一种变革性的、 协作的AD方法，利用NIA资助的长期纵向队列，并且高度 响应国家阿尔茨海默氏症计划。这些新颖的见解将阐明具有潜力的途径。 针对新的治疗靶点，将为社区创建一个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。

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.