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: 10454262
• 负责人: David John Irwin
• 金额: $ 247.98万
• 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/10454262
• 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; Persons; 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.

额颞叶变性（FTD）是一种研究不足的临床神经退行性疾病， 老年痴呆症（AD）是65岁以下人群中常见的痴呆症。最常见的病理 与FTD相关的是由~43的反式DNA/RNA结合蛋白引起的额颞叶变性 kD（TDP-43（FTLD-TDP）），这也是绝大多数患有 肌萎缩侧索硬化症（FTD-ALS）谱系疾病的共同发生，以及年龄的关键力量- 相关疾病，如边缘优势年龄相关TDP-43脑病（LATE）。自从发现了一个 TDP-43病理学在人类疾病中的作用，在实验细胞和 疾病的动物模型。然而，人脑有许多独特的特性， 人类临床疾病，不容易在这些实验模型中复制。知识方面的主要差距 从而限制了改善疾病的治疗试验的发展。其中之一就是我们对 异常TDP-43在分子水平上的积累和进展的病理生理后果， 水平在微观水平上，一个主要的限制是大多数TDP-43累积的患者具有散发性的 这种疾病只能在尸检中可靠地确定，尽管约20%的病例有家族性FTLD（fFTLD）， 生活中已知的病理学我们在将这些知识转化为宏观层面方面受到限制，其中FTLD- TDP病理表现在人类中，具有异质性临床特征，如情绪 失调和语言障碍，包括运动障碍和非运动障碍。此外， 了解导致疾病进展率高度变化的因素。在五部小说中， 独立但协同的项目和支持每个项目的五个核心，这个独特的， 多学科的计划项目资助（PPG）采用创新的视角来研究 TDP-43相关的神经网络在分子，微观和宏观水平的崩溃， 人类我们假设，我们新颖的、整合良好的网络视角将填补以下方面的主要空白： 通过阐明对异常TDP-43的病理生理学的机械见解， 疾病进展的相关模式，并提供了一个新的角度来识别 在生命过程中积累TDP-43病理及其纵向过程。这一提议符合 FTD在2019年阿尔茨海默病及相关疾病（ADRD）峰会上的最高优先事项。通过 专注于大脑功能的分子、微观和宏观层面上的神经网络破坏， 我们的多学科网络方法将阐明异常TDP-43的病理生理学和传播， 人类，并检查TDP-43病理学对痴呆症患者生活中临床疾病的影响， 使用新的方法来提高我们对TDP-43在人类中病理学的机械理解， 保持最高水平的科学严谨性，并为治疗试验等紧急临床需求做出贡献。