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：
10227995
负责人：
Christopher Jackson
金额：
$ 80.21万
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/10227995
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 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 Neuraxis 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 analysis pipeline base burden of illness case control 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 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 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.

肌萎缩性外侧硬化症（ALS）和额颞痴呆（FTD）是致命且不可治疗的一部分疾病谱是通过中枢神经系统在TDP-43聚集的各种表现中统一的疾病谱（CNS）组织。多达50％的运动功能障碍患者也出现认知缺陷，有15％的患者 Frank FTD，但是不同的临床和病理表现的分子机制仍然存在理解不佳。在我们最近的工作中，我们证明了爱丁堡的认知和行为ALS屏幕（ECA）是运动外TDP-43病理学的良好临床预测指标。具体而言，ECAS子域分数与与影响认知相对应的大脑区域中TDP-43夹杂物的分布相关域。但是，在一个区域中存在TDP-43病理学并不能预测相关的认知缺陷与那个区域。我们认为，认知能力可能还有其他更敏感的神经病理学相关性剩下的参与待定，并假设这些其他病理特征包括核质蛋白错误定位，基因表达中的扰动和功能失调的细胞细胞相互作用 - 可能与特定的认知障碍更紧密地相关额叶皮质区域。我们将通过对后期的全面多词分析来检验这一假设。识别的验尸组织1）如何在细胞类型特异性亚群和细胞间相互作用的差异在ALS-FTD病例和对照之间与蛋白质聚集和错误定位有关，以及2）这些如何差异与ALS-FTD的认知障碍有关。我们将使用空间解决蛋白质组学（AIM 1）和转录组（AIM 2）测量，以分析临床病理分层从认知上的背外侧前额叶皮质组织样品（特别是Brodmann区域BA44和BA46） ALS患者和年龄/性别匹配的对照受损。通过使用多种方法同时绘制所有相互作用的细胞亚群的空间转录组和蛋白质组地区，我们的目的是阐明可能揭示新的诊断和治疗靶标。我们以前已经实施了空间转录组学（ST）在脊髓上确定各种细胞类型的亚群中的区域差异，这些细胞类型变化为疾病动力学的功能。这些数据将直接与病理量度有关（例如，病理学家包含）。为了整合和分析跨模式之间数据之间的关系，我们将开发一个用于对疾病负担的多模式多摩尔措施进行统一分析的计算框架（AIM 2）。最后，我们将实施高度多重的免疫成像，以在独立的ALS-中验证我们的发现 FTD队列（AIM 3）。我们跨实验方式的综合分析（单细胞RNA-seq，空间转录组学，多重成像和蛋白质组学）将产生疾病病理学和阐明在不同细胞群体内外协调的神经营养和神经毒性功能。