Project 3: 3-D Molecular Atlas of cerebral amyloid angiopathy in the aging brain with and without co-pathology

项目 3：有或没有共同病理的衰老大脑中脑淀粉样血管病的 3-D 分子图谱

基本信息

批准号：
10555899
负责人：
JULIE A. SCHNEIDER
金额：
$ 51.29万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/10555899
关键词：
3-Dimensional Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Amyloid Amyloid beta-Protein Antibodies Atlases Autopsy Blood Vessels Brain region Cerebral Amyloid Angiopathy Chromosome Mapping Complement Data Dementia Development Dissociation Elderly Elements Environment Gene Expression Gene Expression Profile Generations Genes Goals Human Image Immunohistochemistry Impaired cognition In Situ Hybridization Indirect Immunofluorescence Individual Leptomeninges Lewy Bodies Maps Measurement Measures Methods Modeling Molecular Molecular Profiling Nerve Degeneration Occipital lobe Pathogenesis Pathology Phase Predisposition Prefrontal Cortex Proteins Research Research Project Grants Resolution Sampling Severities Spatial Distribution Standardization Superior temporal gyrus Temporal Lobe Thick Time Tissue Sample Tissues Vascular Diseases Work abeta deposition aged aging brain brain tissue cell type comorbidity computer framework genome-wide human tissue misfolded protein neuropathology neurovascular unit non-demented novel protein TDP-43 protein expression scale up single nucleus RNA-sequencing tau Proteins transcriptome transcriptomics transmission process

项目摘要

PROJECT 3: PROJECT SUMMARY/ABSTRACT Cerebral amyloid angiopathy (CAA) is an age-associated vasculopathy in which there is deposition of amyloid-β protein in the walls of leptomeningeal and parenchymal blood vessels. It can be seen in association with Alzheimer’s disease- neuropathologic change (AD-NC), as well as in isolation. In this study, we focus on how CAA alters the local cellular environment in three distinct regions of the brain that are known to have variable susceptibility to CAA: superior temporal gyrus, dorsolateral prefrontal cortex, and calcarine cortex. We will compare CAA in isolation and in association with increasing burden of AD-NC. There is extremely limited molecular data on how CAA can modify the local cellular environment in aging, although we know CAA can cause cognitive decline in the absence of any other proteinopathy, but can also exacerbate the cognitive decline with proteinopathy. Thus, the overarching goal of this project is to generate a spatial atlas of cell types and molecular signatures in cases with CAA and variable severities of Alzheimer’s Disease- Neuropathologic Change (AD-NC) to assess short- and long-range, and interactive effects of multiple pathologies on cellular composition and signatures from post-mortem human brain tissue. We hypothesize that CAA has local effects on the cell type composition and protein signature nearby, affecting all elements of the neurovascular unit (NVU), and that the effects of CAA are exacerbated by the presence of comorbid AD proteinopathies. For this project we propose a combination of novel but demonstrably scalable protein and gene expression approaches, to study large volumes (300-micron thickness) of human tissue with combinations of CAA with and without AD-NC. This will allow for the generation of a high-resolution atlas of cell types and gene expression signatures in aged human brain tissue that relate to CAA, complementing many of the existing and ongoing bulk and single-nucleus RNA-seq studies in the field of human neurodegeneration research

项目3：项目摘要/摘要脑淀粉样血管病（CAA）是一种与年龄相关的血管病，其中存在沉积瘦脑和副血管壁中的淀粉样蛋白蛋白。可以看到随着阿尔茨海默氏病 - 神经病理学变化（AD-NC）以及孤立。在这项研究中，我们将重点关于CAA如何改变大脑三个不同区域的局部细胞环境 CAA的可变敏感性：上临时回，背外侧前额叶皮层和钙质皮层。我们将孤立地比较CAA，并与AD-NC的Burnen增加。有极度关于CAA如何改变衰老中局部细胞环境的分子数据有限，尽管我们知道在没有任何其他蛋白质病的情况下，CAA会导致认知能力下降，但也会加剧蛋白质病的认知能力下降。那个项目的总体目标是生成空间地图集在患有CAA的病例和阿尔茨海默氏病的严重程度变化的情况下，细胞类型和分子特征神经病理学变化（AD-NC）评估多重的短期和远程效果病后人脑组织的细胞组成和特征的病理。我们假设该CAA对附近的细胞类型组成和蛋白质特征有局部影响，影响了所有元素神经血管单元（NVU）的作用，CAA的影响因合并症的存在而加剧 AD蛋白质。对于这个项目，我们提出了一种新颖但明显可扩展的蛋白质的组合和基因表达方法，研究人体组织的大量（300微米厚度） CAA与AD-NC的组合。这将允许生成一个高分辨率地图集与CAA相关的老年人脑组织中的细胞类型和基因表达特征人类领域的许多现有和正在进行的散装和单核RNA-seq研究神经变性研究