MIRIAD - Multiplexed Imaging of Resilience In Alzheimers Disease

MIRIAD - 阿尔茨海默病恢复力的多重成像

• 批准号: 9439172
• 负责人: Robert michael Angelo
• 金额: $ 93.48万
• 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: 2017-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9439172
• 关键词: Abbreviations; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-Protein; Apolipoprotein E; Area; Biology; Blood Vessels; Brain; Cells; Cessation of life; Chronic Disease; Clinical; Cognitive; Color; Communities; Consumption; Data; Databases; Dementia; Disasters; Disease; Electrons; Equipment; Financial compensation; Fluorescence-Activated Cell Sorting; Fusiform gyrus; Generations; Genetic; Genetic Risk; Genomics; Healthcare Systems; Hippocampus (Brain); Human; Image; Image Analysis; Immunohistochemistry; Individual; Inferior; Investigation; Knowledge; Lobule; Longitudinal cohort study; Measures; Modeling; Molecular; Multiplexed Ion Beam Imaging; Nerve Degeneration; Neurofibrillary Tangles; Neuroglia; Neurons; Online Systems; Parietal; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Plant Roots; Population; Proteins; Proteomics; Public Health; Research; Research Infrastructure; Resistance; Resolution; Resources; Risk; Role; Scientist; Senile Plaques; Slide; Spectrometry, Mass, Secondary Ion; Surface; Synapses; Testing; Universities; Washington; abeta accumulation; aging population; collaborative approach; data sharing; disability; disease-causing mutation; high dimensionality; imaging platform; imaging study; innovation; insight; instrumentation; learning strategy; molecular imaging; molecular phenotype; nanometer; neuroinflammation; neuropathology; new therapeutic target; next generation; novel; paired helical filament; predictive modeling; predictive signature; presenilin; presenilin-1; presenilin-2; resilience; response to injury; risk variant; symposium; tissue resource

ABSTRACT Alzheimer's disease (AD) remains a leading cause of disability and death in the US and major global public health problem due to rise in aging population resulting in untold suffering, and severe challenges to health care systems and economies is certain. Solutions will come only from innovative research. Our application is highly responsive to this urgent scientific need by proposing to leverage an innovative molecular imaging platform invented at Stanford, multiplexed ion beam imaging (MIBI). We will determine the high dimensional cellular and subcellular protein-level expression, interaction, and localization for AD-relevant molecules identified by genomic and proteomic studies in resilience and pathologic states using human brain sections from an ongoing proteomic investigation of AD. We hypothesize that in-depth, stage-specific phenotypic signatures extracted from these unique groups will provide insight into the modifiable factors that endorse the protective mechanisms of brain reserve. We will test our hypothesis through three Specific Aims: (1) Establish a subcellular, phenotypic framework of vulnerable and resistant brain areas. Next-generation MIBI equipment will be used to rigorously image 30+ proteins simultaneously; targets marking subtypes of neurons, synapses, non-neuronal cells, neuro-inflammatory, and vascular components will be concurrently measured. (2) Reveal cognitive resilience multiplexed phenotypes. Using approaches we have successfully applied in other single cell studies, we will analyze multiplexed imaging data with statistical deep learning methods already established in our lab to identify topological, cellular, and molecular phenotypic differences among resilient, co- morbid, and AD dementia. (3) Implement a shared data repository. The power of multiplexed imaging in biology is its ability to reveal co-localization or mutual exclusivity to infer regulatory roles and gain mechanistic insight. To disseminate hundreds of these images from our proposed highly multiplexed study, we will create a web-based portal, using already established infrastructure, where all of the images from this study can be accessed, multi-color overlays generated ad hoc, and all the features will be shared freely.

抽象的 阿尔茨海默氏病（AD）仍然是美国和全球主要公众残疾和死亡的主要原因 健康问题由于人口衰老而引起的造成无数痛苦，以及对健康的严重挑战 护理系统和经济是可以肯定的。解决方案仅来自创新研究。我们的申请是 通过提议利用创新的分子成像，对这种紧急科学需求高度敏感 在斯坦福大学发明的平台，多路复用离子束成像（MIBI）。我们将确定高维度 细胞和亚细胞蛋白水平表达，相互作用和与AD相关的分子的定位 通过人脑切片在弹性和病理状态中的基因组和蛋白质组学研究确定 来自对AD的蛋白质组学研究。我们假设这是深入的，特定阶段的表型 从这些独特的群体中提取的签名将提供对认可的可修改因素的见解 大脑储备的保护机制。我们将通过三个特定目的来检验我们的假设：（1）建立 易受伤害和抗性大脑区域的亚细胞，表型框架。下一代MIBI设备 将同时使用严格的30+蛋白质图像；标记神经元，突触的亚型的目标 将同时测量非神经元细胞，神经炎症和血管成分。 （2）揭示 认知弹性多重表型。使用方法我们已成功应用于其他单一 细胞研究，我们将使用统计深度学习方法分析多路复用成像数据 在我们的实验室中建立，以识别弹性，共同的拓扑，细胞和分子表型差异 病态和痴呆症。 （3）实现共享数据存储库。多重成像的力量 生物学是其揭示共定位或相互排他性来推断调节作用并获得机理的能力 洞察力。为了将数百个这些图像从我们提出的高度多路复用研究中传播出来，我们将创建一个 基于Web的门户，使用已经建立的基础架构，本研究中的所有图像都可以是 访问，多色叠加层生成的临时，所有功能将自由共享。