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.

项目总结/摘要 LATE-NC（43 kDa的边缘优势年龄相关反式反应DNA结合蛋白[TDP-43]） 脑病神经病理学变化），一种最近认识到的TDP-43蛋白病形式，是第三种 阿尔茨海默病神经病理学变化（ADNC）后痴呆的最有影响力的原因， 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，LATE-NC特异性的风险位点，以及与其他人共享的风险位点。 常见的导致痴呆的蛋白质病我们小组的一项转录组学研究表明， 调节异常是LATE-NC的重要病理生理过程。然而，分子和细胞 LATE-NC的基础在很大程度上仍然未知：我们甚至没有体外/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 后来，NC在活人身上。定义LATE-NC背后的分子和细胞变化是一个先决条件 涉及开发可翻译的体外/体内疾病模型和鉴定生物标志物/治疗靶标。这 2022年NIH AD相关痴呆（ADRD）峰会承认了关键的知识差距， 其提出了研究与LATE-NC相关的分子变化的高优先级建议。 因此，该建议旨在定义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被认为起源于大脑区域。我们的核心假设是， 在杏仁核中，内-溶酶体失调，RNA代谢改变，胶质功能障碍和神经元丢失 LATE-NC病理生理学的基础。为了检验中心假设，我们建议生成和分析 转录组、蛋白质组和单核多组（转录组和染色质可及性）数据来自 死后杏仁核样本来自广泛表征的宗教秩序研究和拉什， 记忆和衰老项目参与者（n=480）。我们会致力达致以下三个具体目标：第一， 确定LATE-NC的转录基础。第二，我们将确定蛋白质组签名， 最近-NC。第三，我们将定义LATE-NC的单细胞景观。我们将使用统计建模 推断因果关系的方法。我们将考虑性别特异性效应和以下因素的混杂效应： 在整个研究期间，共病ADNC病理学。该项目的预期成果将提名蛋白质 生物标志物靶向并定义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，并最终靶向 治疗学大规模的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 研究远远超出了这一建议。因此，这个项目有可能从根本上提高我们的能力 诊断、治疗并最终预防痴呆症，包括晚期痴呆症。