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.

项目概要/摘要 LATE-NC（边缘系统主导的年龄相关反应反应 DNA 结合蛋白，43 kDa [TDP-43] 脑病神经病理改变）是最近公认的 TDP-43 蛋白病的第三种形式 继阿尔茨海默病神经病理改变 (ADNC) 后导致痴呆的最有影响力的原因 脑血管疾病，占所有老年人痴呆病例的 15-20% 遗传相关。 我们小组和其他人的研究揭示了独特的、LATE-NC 特定的风险位点以及与其他人共享的风险位点 我们小组的一项转录组学研究涉及内溶酶体。 然而，失调是 LATE-NC 的一个重要的病理生理过程。 LATE-NC 的基础在很大程度上仍然未知：我们甚至不具备体外/体内开发的知识 体内疾病模型或指定目标途径，因此，我们无法诊断、治疗或预防 定义活人中 LATE-NC 的分子和细胞变化是先决条件。 开发可转化的体外/体内疾病模型并确定生物标志物/治疗靶点。 2022 年 NIH AD 相关痴呆症 (ADRD) 峰会承认了关键的知识差距， 其中高度优先建议研究与 LATE-NC 相关的分子变化。 因此，该提案旨在定义 LATE-NC 的转录组学、蛋白质组学和细胞基础 在人类杏仁核中，LATE-NC 被认为起源于该大脑区域，我们的中心假设是， 杏仁核、内溶酶体失调、RNA 代谢改变、神经胶质功能障碍和神经元损失 为了检验中心假设，我们建议生成并分析。 转录组、蛋白质组和单核多组（转录组和染色质可及性）数据 来自广泛表征的宗教团体研究和 Rush 的死后杏仁核样本 记忆与衰老项目参与者（n=480）我们将追求以下三个具体目标：首先，我们将 确定 LATE-NC 的转录组学基础 其次，我们将确定 LATE-NC 的蛋白质组学特征。 第三，我们将使用统计建模来定义 LATE-NC 的单细胞景观。 我们将考虑性别特异性效应和混杂效应。 该项目的预期结果将提名蛋白质。 生物标志物目标并定义 LATE-NC 的合理上游和下游事件。这些结果将指导。 我们未来的研究将开发体外和可能的体内 LATE-NC 模型，并最终有针对性 大规模杏仁核多组学数据将与科学界广泛共享 支持众多 ADRD 研究项目，确保对神经退行性疾病产生重大持久影响 研究远远超出了这个建议，因此这个项目有潜力从根本上提高我们的能力。 诊断、治疗并最终预防痴呆症，包括晚期。