Project 4: Integrative analysis of spatial molecular features and clinico-pathological characteristics

项目4：空间分子特征与临床病理特征的综合分析

• 批准号: 10555900
• 负责人: PHILIP L DE JAGER
• 金额: $ 160.25万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10555900
• 关键词: 3-Dimensional; Affect; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; American; Amyloid; Brain; Categories; Cell Nucleus; Cells; Cerebral Amyloid Angiopathy; Characteristics; Clinical; Cognitive; Complement; Data; Data Analyses; Data Set; Dedications; Dimensions; Elderly; Ensure; Evaluation; Genes; Genetic Variation; Goals; Heterogeneity; Impaired cognition; Impairment; Individual; Investigation; Knowledge Portal; Lewy Bodies; Link; Microglia; Molecular; Neocortex; Neurodegenerative Disorders; Neuropsychology; Not Hispanic or Latino; Older Population; Outcome; Participant; Pathologic; Pathology; Planet Mars; Population; Prefrontal Cortex; Proteins; Proteomics; Research Personnel; Resources; Risk Factors; Role; Sample Size; Sampling; Sister; Source; Stains; Superior temporal gyrus; Testing; Tissue Sample; Tissues; Variant; aging brain; brain tissue; cognitive performance; cohort; data framework; demented; design; distributed data; drug development; epigenomics; insight; multiple omics; neocortical; neuropathology; next generation; novel; programs; protein TDP-43; spatial integration; tau Proteins; trait; transcriptome sequencing; transcriptomics; whole genome

PROJECT 4: PROJECT SUMMARY/ABSTRACT Over the past two decades, we have come to appreciate that the aging brain harbors a multiplicity of neuropathologies and that AD proteinopathy often coexists with other pathologic features such as Lewy Bodies and TDP43 proteinopathy. However, the impact of co-occurrence remains poorly understood. Co-occurrence also increases with advancing age, highlighting that age is a critical risk factor for all of the neuropathologies that we examine in our 3D Aging & Alzheimer Brain Program. This project aims to profile brain tissue from a large (n=300) set of diverse individuals to create a complementary resource to those produced in Projects 1-3. Here, we profile a random sample of participants in the RUSH cohorts to capture the heterogeneity seen in the older population. In addition, we leverage their detailed ante-mortem characterization of neuropsychologic function to relate molecular data and the cellular attributes identified in Projects 1-3 to cognitive decline, the ultimate, clinically meaningful outcome in AD. Amyloid, tau and CAA all influence cognitive performance in the ROSMAP cohorts. In particular, preliminary results from single nucleus RNAseq data suggest a critical role for a new microglial subtype, Microglia 13 (Mi13), in AD and CAA. Thus, the new 3D dataset that we propose to generate and distribute as part of this Project will enable us to test a specific hypothesis that we have today and to uncover new insights from unbiased analyses. Our samples also include 100 African-American (AA) participants from the ROSMAP and MARS cohorts that have the same clinicopathologic traits and multiomic brain data as the 200 non-hispanic white (NHW) participants. Here, we therefore explicitly complement the other Projects, which focus on Non-Hispanic White participants, by sampling a large number of AA subjects so that we can assess the generalizability of our findings to a broader population. The integrated analysis of the data in this project with the attributes identified in the other three projects will lead to a new set of candidate proteins involved in cognitive decline, which will be used to profile a replication cohort of an independent set of participants. Thus, the key goals for us are (1) the creation of an easily repurposable, high-impact dataset, (2) the testing of a current hypothesis and (3) assembly of an important set of new insights into AD and CAA that can be used to seed further investigation, including some dedicated to AA. Overall, this Project creates a unique reference data set that can be repurposed for a multitude of uses and leveraged to design a next generation of spatial transcriptomic (ST) studies for other neurodegenerative diseases.

项目4：项目摘要/摘要 在过去的二十年中，我们已经意识到，衰老的大脑具有多种 神经病理学和AD蛋白质病经常与其他病理特征（例如Lewy身体）共存 和TDP43蛋白质病。但是，共同出现的影响仍然很少了解。共发生 随着年龄的增长，还会增加，强调年龄是所有神经病理学的关键危险因素 我们在3D衰老和阿尔茨海默氏症脑计划中检查。该项目旨在从大型 （n = 300）一组不同的个体，为项目1-3中生产的资源创造互补资源。这里， 我们介绍了Rush队列中参与者的随机样本，以捕获较老的异质性 人口。此外，我们利用它们的详细的神经心理学功能的详细的事前表征 相关的分子数据和项目1-3中确定的细胞属性与认知能力下降，最终， AD中的临床意义有意义。淀粉样蛋白，tau和CAA都影响了Rosmap中的认知表现 同伙。特别是，单核RNASEQ数据的初步结果表明，新的至关重要的作用 小胶质细胞亚型，小胶质细胞13（MI13），AD和CAA。因此，我们建议生成的新3D数据集 并作为该项目的一部分分发将使我们能够检验我们今天有的特定假设并发现 无偏分析的新见解。我们的样本还包括来自来自的100名非裔美国人（AA）参与者 Rosmap和Mars同伙具有与200 非西班牙裔白人（NHW）参与者。因此，我们明确补充其他项目，这些项目的重点 关于非西班牙裔白人参与者，通过抽样大量的AA受试者，以便我们可以评估 我们的发现对更广泛的人群的概括性。与该项目中数据的集成分析 其他三个项目中确定的属性将导致一组新的候选蛋白参与认知 下降，将用于介绍一组独立参与者的复制队列。因此，钥匙 我们的目标是（1）创建易于重新验证的高影响力数据集的创建，（2）当前的测试 假设和（3）组装一组重要的AD和CAA的新见解，可用于种子 进一步的调查，包括一些专门针对AA的人。总体而言，该项目创建了独特的参考数据集 可以重新使用多种用途，并利用以设计下一代空间转录组 （ST）其他神经退行性疾病的研究。