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Integrating Spatial Multi-omics and Clinical Covariates to Identify Mechanisms of Disease in ALS-FTD

整合空间多组学和临床协变量以确定 ALS-FTD 的疾病机制

基本信息

批准号：
10599958
负责人：
Christopher Jackson
金额：
$ 76.75万
依托单位：
NEW YORK GENOME CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599958
关键词：
ALS patients Adopted Affect Age Amyotrophic Lateral Sclerosis Atlases Autopsy Behavioral Biological Markers Brain Brain region Brodmann&apos s area Cell Communication Cells Central Nervous System Clinic Clinical Cognitive Cognitive deficits Computing Methodologies Data Disease Event Fostering Frontotemporal Dementia Functional disorder Gender Gene Expression Gene Expression Profile Goals Heterogeneity Histology Image Impaired cognition Indirect Immunofluorescence Individual Link MFGE8 gene Maps Measurement Measures Methods Modality Molecular Motor Neurodegenerative Disorders North America Outcome Pathogenesis Pathologic Pathology Pathway interactions Patients Phenotype Population Prefrontal Cortex Proteins Proteome Proteomics Resolution Sensitivity and Specificity Spinal Cord Statistical Models Sudden Death TDP-43 aggregation Testing Tissue Sample Tissues Work burden of illness cell type clinical predictors clinical subtypes cognitive change cognitive function cognitive testing cohort computational pipelines computer framework data acquisition data integration frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis functional disability high dimensionality immune imaging motor disorder multimodality multiple omics multiplexed imaging neuropathology neurotoxic new therapeutic target novel novel diagnostics precision medicine protein TDP-43 protein aggregation regional difference single-cell RNA sequencing spatial integration stem transcriptome transcriptomics treatment strategy

项目摘要

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a fatal and untreatable disease spectrum that is unified by a diverse presentation of TDP-43 aggregation across central nervous system (CNS) tissue. Up to 50% of patients with motor dysfunction also present with cognitive deficits and 15% have frank FTD, but the molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. In our recent work, we have shown that the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) is a good clinical predictor of extra-motor TDP-43 pathology. Specifically, ECAS subdomain scores correlate with the distribution of TDP-43 inclusions in brain regions corresponding to the affected cognitive domains. However, the presence of TDP-43 pathology in a region is not predictive of cognitive deficits associated with that region. We posit that there may be other, more sensitive, neuropathological correlates of cognitive involvement that remain to be identified, and hypothesize that additional pathological features--including nucleocytoplasmic protein mislocalization, perturbations in gene expression, and dysfunctional cell-cell interactions--may correlate more closely with domain-specific cognitive impairment corresponding to a particular region of the frontal cortex. We will test this hypothesis through a comprehensive multi-omic analysis of post- mortem tissue that identifies 1) how differences in cell type-specific subpopulations and intercellular interactions between ALS-FTD cases and controls relate to protein aggregation and mislocalization and 2) how these differences relate to cognitive impairment in ALS-FTD. We will accomplish these goals using spatially resolved proteomic (Aim 1) and transcriptomic (Aim 2) measurements to analyze clinico-pathologically stratified dorsolateral prefrontal cortical tissue samples (specifically, Brodmann areas BA44 and BA46) from cognitively impaired ALS patients and age/gender matched controls. By using a combination of approaches to simultaneously map the spatial transcriptome and proteome of all interacting cellular subpopulations in these regions, our aim is to elucidate the origins and temporal dynamics of inter- and intra-cellular activities that may reveal novel diagnostic and therapeutic targets. We have previously implemented Spatial Transcriptomics (ST) on the spinal cord to identify regional differences within subpopulations of various cell types that vary as a function of disease dynamics. These data will be directly tied to measures of pathology (e.g., pathognomonic inclusions). To integrate and analyze relationships between data across modalities, we will develop a computational framework for harmonized analysis of multi-modal, multi-omic measures of disease burden (Aim 2). Finally, we will implement highly multiplexed immuno-imaging to validate our findings in an independent ALS- FTD cohort (Aim 3). Our integrated analysis across experimental modalities (single cell RNA-seq, spatial transcriptomics, multiplexed imaging and proteomics) will yield an unprecedented view of disease pathology and elucidate neurotrophic and neurotoxic functions that are coordinated within and across different cell populations.

肌萎缩侧索硬化症（ALS）和额颞叶痴呆症（FTD）是致命的和不可治愈的疾病的一部分。通过TDP-43在中枢神经系统中聚集的多样性表现而统一的疾病谱 (CNS)组织.高达50%的运动功能障碍患者也存在认知缺陷，15%的患者坦率的FTD，但不同的临床和病理表现的分子机制仍然存在不太了解。在我们最近的工作中，我们已经表明爱丁堡认知和行为ALS筛查（ECAS）是运动外TDP-43病理学的良好临床预测因子。具体来说，ECAS子域得分与TDP-43包涵体在对应于受影响的认知功能的脑区域中的分布相关。域.然而，TDP-43病理学在一个区域的存在并不能预测与脑梗死相关的认知缺陷。与该地区。我们认为，可能有其他更敏感的神经病理学相关的认知参与仍然有待确定，并假设其他病理特征-包括核质蛋白质错误定位、基因表达紊乱和细胞-细胞功能障碍互动-可能与特定领域的认知障碍更密切相关，额叶皮层的区域。我们将通过一个全面的多组学分析后，鉴定1）细胞类型特异性亚群和细胞间相互作用的差异 ALS-FTD病例和对照之间的差异与蛋白质聚集和错误定位有关，以及2）这些差异与ALS-FTD中的认知障碍有关。我们将使用空间分辨的蛋白质组学（Aim 1）和转录组学（Aim 2）测量，以分析临床病理分层背外侧前额叶皮质组织样本（具体而言，Brodmann区域BA44和BA46），受损的ALS患者和年龄/性别匹配的对照。通过使用各种方法，同时绘制这些细胞中所有相互作用的细胞亚群的空间转录组和蛋白质组，区域，我们的目的是阐明起源和时间动态的细胞间和细胞内的活动，揭示新的诊断和治疗靶点。我们之前已经实现了空间转录组学（ST）以确定不同细胞类型亚群内的区域差异，疾病动力学的作用。这些数据将直接与病理学指标（例如，病征内含物）。为了集成和分析跨模态数据之间的关系，我们将开发一个疾病负担的多模式、多经济学指标协调分析的计算框架（目的 2）。最后，我们将实施高度多重免疫成像，以验证我们在一个独立的ALS研究中的发现。 FTD队列（目标3）。我们跨实验模式（单细胞RNA-seq，空间转录组学、多重成像和蛋白质组学）将产生前所未有的疾病病理学观点，阐明神经营养和神经毒性功能，协调内和跨不同的细胞群体。