From cells to complex syndromes: using networks to understand heterogeneity in TDP-related frontotemporal degeneration and aging

从细胞到复杂综合征：利用网络了解 TDP 相关额颞叶退化和衰老的异质性

• 批准号: 10261330
• 负责人: MURRAY GROSSMAN
• 金额: $ 246.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10261330
• 关键词: Adopted; Advisory Committees; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Disease Models; Animal Model; Area; Autopsy; Biological Markers; Biometry; Brain; Brain region; Cell model; Cells; Clinical; Clinical Pathology; Collection; Complex; DNA; Dementia; Development; Diagnosis; Discipline; Disease; Disease Progression; Elements; Ensure; Experimental Models; Family; Frontotemporal Lobar Degenerations; Functional disorder; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; Image; Knowledge; Lead; Life; Mediating; Microscopic; Molecular; Nerve Degeneration; Nervous System Physiology; Neurons; Outcome; Pathologic; Pathology; Pathway Analysis; Patients; Pattern; Prognosis; Program Research Project Grants; Progressive Disease; Property; RNA-Binding Proteins; Resources; Role; Science; Syndrome; System; Transact; Translating; Work; age related; emotion dysregulation; experimental study; frontotemporal degeneration; frontotemporal lobar dementia-amyotrophic lateral sclerosis; grasp; human disease; improved; in vivo; innovation; insight; language impairment; limbic-predominant age-related TDP-43 encephalopathy; longitudinal course; motor disorder; multidisciplinary; neural network; novel; programs; protein TDP-43; relating to nervous system; single-cell RNA sequencing; symposium; therapy development; tool; treatment trial

Frontotemporal degeneration (FTD) is an understudied clinical neurodegenerative condition that is the most common dementia after Alzheimer disease (AD) in people younger than 65. The most common pathology associated with FTD is frontotemporal lobar degeneration due to transactive DNA/RNA binding protein of ~43 kD (TDP-43 (FTLD-TDP), and this is also the underlying pathology in the vast majority of patients who have co-occurring amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders as well as a critical force in age- related disorders such as limbic-predominant age-related TDP-43 encephalopathy (LATE). Since discovering a role for TDP-43 pathology in human disease, important progress has been made in experimental cellular and animal models of disease. However, the human brain has many unique properties associated with distinctly human clinical disorders that are not easily replicated in these experimental models. Major gaps in knowledge thus constrain the development of disease-modifying treatment trials. Among these is our limited knowledge of the pathophysiologic consequences of the accumulation and progression of abnormal TDP-43 at a molecular level. At a microscopic level, a major limitation is that most patients with accumulating TDP-43 have sporadic disease that can be identified reliably only at autopsy, although ~20% of cases have familial FTLD (fFTLD) with known pathology during life. We are limited at translating this knowledge to a macroscale level where FTLD- TDP pathology is manifested in humans with heterogeneous clinical features as diverse as emotional dysregulation and impaired language both with and without a motor disorder. Moreover, there is limited knowledge of the factors contributing to the highly varying rates of disease progression. In five novel, independent but synergistic Projects and five Cores that support each of the Projects, this unique, multidisciplinary, Program Project Grant (PPG) adopts the innovative perspective of investigating the TDP-43-associated breakdown of neural networks at molecular, microscopic and macroscale levels in humans. We hypothesize that our novel, well-integrated, network perspective will fill major gaps in knowledge by elucidating mechanistic insights into the pathophysiology of abnormal TDP-43 and the associated pattern of disease progression, and offer a fresh perspective on the identification of accumulating TDP-43 pathology during life and its longitudinal course. This proposal is consistent with the highest priorities for FTD at the 2019 Alzheimer’s Disease and Related Disorders (ADRD) summit. By focusing on disruption of neural networks at molecular, microscopic and macroscale levels of brain functioning, our multidisciplinary network approach will elucidate the pathophysiology and spread of abnormal TDP-43 in humans, and examine the consequences of TDP-43 pathology for clinical disease during life in dementia and aging using fresh approaches to improve our mechanistic understanding of TDP-43 pathology in humans while maintaining the highest level of scientific rigor and contributing to urgent clinical needs such as treatment trials.

额颞变性（FTD）是一种理解的临床神经退行性疾病，是最多的 年龄少于65岁的患者阿尔茨海默氏病（AD）的常见痴呆症。最常见的病理 与FTD相关的是由于交易DNA/RNA结合蛋白〜43 KD（TDP-43（FTLD-TDP），这也是绝大多数患者的潜在病理 共同发生的肌萎缩性侧面硬化症（FTD-ALS）光谱疾病以及年龄的关键力量 相关疾病，例如与年龄相关的TDP-43脑病（晚）。自发现一个 TDP-43病理在人类疾病中的作用，在实验性细胞和 疾病动物模型。但是，人的大脑具有许多独特的特性 在这些实验模型中不容易复制的人类临床疾病。知识的主要差距 因此，限制了修改疾病的治疗试验的发展。其中包括我们对 异常TDP-43在分子上的积累和进展的病理生理后果 等级。在显微镜水平上，主要限制是大多数累积TDP-43的患者偶然 仅在尸检时才能可靠地鉴定出来的疾病，尽管约有20％的病例患有家庭FTLD（FFTLD） 人生中已知的病理。我们只能将这些知识转化为宏观级别，而FTLD- TDP病理学表现在具有异质临床特征的人类中的潜水 有或没有运动障碍的语言失调和语言受损。而且，有限 了解导致疾病进展率高度变化的因素。在五本小说中 独立但协同的项目和五个支持每个项目的核心，这个独特， 多学科计划项目赠款（PPG）采用了调查的创新观点 在分子，显微镜和宏观水平上与TDP-43相关的神经网络的分解 人类。我们假设我们的小说，整合，网络的视角将填补主要空白 通过阐明对异常TDP-43和 疾病进展的相关模式，并为识别提供了新的视角 在生活及其纵向过程中累积TDP-43病理。该提议与 FTD在2019年阿尔茨海默氏病和相关疾病（ADRD）峰会上的最高优先事项。经过 专注于分子，显微镜和宏观脑功能水平上的神经元网络的破坏， 我们的多学科网络方法将阐明异常TDP-43在 人类，并检查TDP-43病理学对痴呆症和生命中临床疾病的后果 使用新方法衰老，以提高我们对人类TDP-43病理学的机械理解，而 保持最高水平的科学严谨性，并促进紧急临床需求，例如治疗试验。