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

• 批准号: 10034901
• 负责人: RICHARD A BONNEAU
• 金额: $ 86.72万
• 依托单位: NEW YORK GENOME CENTER
• 依托单位国家: 美国
• 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/10034901
• 关键词: ALS patients; Adopted; Affect; Age; Amyotrophic Lateral Sclerosis; Atlases; Autopsy; Behavioral; Biological Markers; Brain; Brain region; Brodmann' 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

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 (FTD) 是致命且无法治愈的疾病的一部分 中枢神经系统中 TDP-43 聚集的不同表现而统一的疾病谱 （中枢神经系统）组织。高达 50% 的运动功能障碍患者还存在认知缺陷，其中 15% 存在认知缺陷 坦率的 FTD，但不同临床和病理表现背后的分子机制仍然存在 不太了解。在我们最近的工作中，我们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 子域分数 与受影响认知对应的大脑区域中 TDP-43 内含物的分布相关 域。然而，某个区域 TDP-43 病理的存在并不能预测相关的认知缺陷 与该地区。我们假设认知可能存在其他更敏感的神经病理学相关性 仍有待确定的参与，并假设其他病理特征 - 包括 核细胞质蛋白错误定位、基因表达扰动和细胞间功能障碍 相互作用——可能与特定领域对应的认知障碍更密切相关 额叶皮层区域。我们将通过对后研究的全面多组学分析来检验这一假设。 尸检组织可识别 1) 细胞类型特异性亚群和细胞间相互作用的差异 ALS-FTD 病例和对照之间与蛋白质聚集和错误定位相关，以及 2) 这些如何 差异与 ALS-FTD 的认知障碍有关。我们将使用空间分辨来实现这些目标 蛋白质组学（目标 1）和转录组学（目标 2）测量以分析临床病理分层 来自认知的背外侧前额皮质组织样本（特别是布罗德曼区 BA44 和 BA46） 受损的 ALS 患者和年龄/性别匹配的对照。通过使用多种方法的组合 同时绘制这些区域中所有相互作用的细胞亚群的空间转录组和蛋白质组图 区域，我们的目标是阐明细胞间和细胞内活动的起源和时间动态，这些活动可能 揭示新的诊断和治疗靶点。我们之前已经实施过空间转录组学 (ST) 在脊髓上识别不同细胞类型亚群内的区域差异 疾病动态的函数。这些数据将直接与病理学测量相关（例如，病理学测量） 夹杂物）。为了整合和分析跨模式数据之间的关系，我们将开发一个 用于对疾病负担的多模式、多组学测量进行协调分析的计算框架（Aim 2）。最后，我们将实施高度多重免疫成像来验证我们在独立 ALS 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和 阐明不同细胞群内部和之间协调的神经营养和神经毒性功能。