Molecular and cellular underpinnings of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC)

边缘系统主导的年龄相关 TDP-43 脑病神经病理学变化 (LATE-NC) 的分子和细胞基础

• 批准号: 10739186
• 负责人: Hyun-Sik Yang
• 金额: $ 129.6万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739186
• 关键词: Accounting; Affect; Aged, 80 and over; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Astrocytes; Autophagocytosis; Autopsy; Binding Proteins; Biological Assay; Biological Models; Brain; Brain Diseases; Brain region; Cell Nucleus; Cells; Cerebrovascular Disorders; Chromatin; Communities; DNA-Binding Proteins; Data; Dementia; Diagnosis; Disease; Disease model; Elderly; Encephalopathies; Ensure; Event; Functional disorder; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Human; In Vitro; Knowledge; Maps; Mediation; Membrane; Memory; Messenger RNA; Metabolism; Modeling; Molecular; Multiomic Data; Nerve Degeneration; Oligodendroglia; Outcome; Participant; Pathology; Pathway interactions; Patients; Persons; Population; Process; Proteins; Proteomics; Public Health; RNA; RNA metabolism; RNA-Binding Proteins; Recommendation; Repression; Research; Research Project Grants; Sampling; Small Nuclear RNA; Statistical Models; Synapses; Systems Development; Testing; Tissues; Transcript; Transposase; United States; United States National Institutes of Health; age related; biomarker discovery; biomarker identification; candidate marker; causal model; cell type; comorbidity; diagnostic biomarker; epigenome; frontal lobe; genetic association; human data; improved; in vivo; limbic-predominant age-related TDP-43 encephalopathy; multiple omics; myelination; neuron loss; neuropathology; prevent; protein TDP-43; protein biomarkers; proteomic signature; religious order study; response; risk variant; sex; symposium; targeted biomarker; targeted treatment; tau Proteins; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT LATE-NC (limbic-predominant age-related transactive response DNA-binding protein of 43 kDa [TDP-43] encephalopathy neuropathological change), a recently recognized form of TDP-43 proteinopathy, is the third most impactful cause of dementia following Alzheimer’s disease neuropathologic change (ADNC) and cerebrovascular disease, accounting for 15-20% of all dementia cases in older adults. Genetic association studies by our group and others revealed unique, LATE-NC-specific risk loci as well as those shared with other common dementia-causing proteinopathies. A transcriptomic study from our group implicated endo-lysosomal dysregulation as a crucial pathophysiologic process underlying LATE-NC. However, molecular and cellular underpinnings of LATE-NC remain largely unknown: we do not even have the knowledge to develop in vitro/in vivo disease models or nominate target pathways, and as a result, we cannot diagnose, treat, or prevent LATE-NC in living persons yet. Defining molecular and cellular changes underlying LATE-NC is a prerequisite to developing translatable in vitro/in vivo disease models and identifying biomarker/therapeutic targets. This critical knowledge gap has been acknowledged by the NIH AD-Related Dementias (ADRD) Summit in 2022, which made a high-priority recommendation to investigate molecular changes associated with LATE-NC. Therefore, this proposal aims to define the transcriptomic, proteomic, and cellular underpinnings of LATE-NC in the human amygdala, the brain region where LATE-NC is thought to originate. Our central hypothesis is that, in the amygdala, endo-lysosomal dysregulation, altered RNA metabolism, glial dysfunction, and neuronal loss underlie LATE-NC pathophysiology. To test the central hypothesis, we propose to generate and analyze transcriptomic, proteomic, and single-nucleus multiome (transcriptome and chromatin accessibility) data from the post-mortem amygdala samples from the extensively characterized Religious Orders Study and Rush Memory and Aging Project participants (n=480). We will pursue the following three specific aims: First, we will determine the transcriptomic underpinnings of LATE-NC. Second, we will identify the proteomic signature of LATE-NC. Third, we will define the single-cell landscape of LATE-NC. We will use statistical modeling approaches to infer causal relationships. We will consider sex-specific effects and the confounding effect of comorbid ADNC pathology throughout the study. The expected outcomes of this project will nominate protein biomarker targets and define plausible upstream and downstream events of LATE-NC. These results will guide our future studies to develop in vitro and possibly in vivo LATE-NC models and, eventually, targeted therapeutics. The large-scale amygdala multi-omic data will be broadly shared with the scientific community to support numerous ADRD research projects, ensuring a significant lasting impact in neurodegeneration research far beyond this proposal. Therefore, this project has the potential to fundamentally improve our ability to diagnose, treat, and ultimately prevent dementia, including LATE.

项目摘要/摘要 NC晚期（边缘 - 促销年龄相关的交易反应DNA结合蛋白为43 kDa [TDP-43] 脑病神经病理学变化）是最近公认的TDP-43蛋白质病的形式，是第三种 阿尔茨海默氏病神经病理学变化（ADNC）和 脑血管疾病，占老年人所有痴呆病例的15-20％。遗传关联 我们小组和其他人的研究揭示了独特的，特定于NC的风险基因座以及与其他人共享的研究。 引起痴呆症的常见蛋白质病。我们小组的转录组研究实施了内部溶酶体 非调节是NC后期至关重要的重要病理生理过程。但是，分子和细胞 NC后期的基础仍然未知：我们甚至没有知识来发展体外/ 体内疾病模型或提名目标途径，结果，我们无法诊断，治疗或预防 nc晚上在活着的人。定义分子和细胞变化是NC后期是先决条件 开发可翻译的体外/体内疾病模型并鉴定生物标志物/治疗靶标。这 2022年，NIH广告相关痴呆症（ADRD）峰会已经承认了批判知识差距 这提出了高优先级的建议，以研究与NC后期相关的分子变化。 因此，该建议旨在定义NC后期的转录组，蛋白质组学和细胞基础 在人类杏仁核中，人们认为纳入晚期的大脑区域起源。我们的中心假设是， 在杏仁核中，内糖体功能障碍，RNA代谢改变，神经胶质功能障碍和神经元丧失 NC晚期病理生理学基础。为了检验中心假设，我们建议生成和分析 转录组，蛋白质组学和单核多组（转录组和染色质访问性）数据来自 来自广泛特征的宗教命令研究和急忙的验尸后杏仁核样本 内存和老化项目参与者（n = 480）。我们将追求以下三个具体目标：首先，我们将 确定NC后期的转录组基础。第二，我们将确定的蛋白质组学特征 nc晚。第三，我们将定义NC后期的单细胞景观。我们将使用统计建模 推断因果关系的方法。我们将考虑特定性别的效果和混杂效应 整个研究过程中合并症ADNC病理。该项目的预期结果将提名蛋白质 生物标志物的靶标并定义了NC晚期的上游和下游事件。这些结果将指导 我们未来的研究，以在体外发展和可能的体内 - NC模型，并最终成为针对性的 治疗。大规模的杏仁核多摩变数据将与科学界广泛共享 支持众多ADRD研究项目，确保对神经退行性的持久影响 研究远远超出了这一建议。因此，该项目有潜力从根本上提高我们的能力 诊断，治疗和最终预防痴呆症，包括迟到。