The physical biology of neurodegeneration in sporadic Amyotrophic Lateral Sclerosis/Frontotemporal dementia

散发性肌萎缩侧索硬化症/额颞叶痴呆神经退行性变的物理生物学

• 批准号: 10273725
• 负责人: Liam J Holt
• 金额: $ 168.7万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10273725
• 关键词: ALS patients; Address; Adult; Affect; Age; Amyotrophic Lateral Sclerosis; Animal Model; Architecture; Autopsy; Back; Biological Markers; Biology; Biophysics; Brain; Cell Communication; Cell model; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Communication; Complex; Crowding; Disease; Disease Marker; Dissociation; Edema; Environment; Etiology; Event; Extracellular Matrix; Fostering; Frontotemporal Dementia; Functional disorder; Genomics; Goals; Homeostasis; Individual; Inflammation; Injury; Intracellular Transport; Knowledge; Lead; Link; Macromolecular Complexes; Measures; Mechanics; Minority; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Phenotype; Property; Proteins; Proteomics; Shapes; Signal Transduction; Site; Solubility; Stress; Surveys; TDP-43 aggregation; Technology; Testing; Therapeutic; Tissues; Transport Process; Viscosity; Work; age related; biophysical properties; biophysical tools; cell type; cohort; design; extracellular; feeding; frontotemporal lobar dementia-amyotrophic lateral sclerosis; functional disability; human disease; in vivo; innovation; insight; intercellular communication; molecular marker; mouse model; novel; precision medicine; protein TDP-43; protein aggregation; protein protein interaction; proteostasis; sporadic amyotrophic lateral sclerosis; stem; stressor; tool; transcriptomics; treatment strategy

On the sporadic Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (sALS/FTD) clinical spectrum, the aggregation and accumulation of disease-associated proteins such as TDP-43 is a notable neuropathological hallmark, yet we know little about why this highly abnormal event might occur. Although disruptions in multiple cellular processes have been implicated in ALS, 3 critical gaps in knowledge remain: 1) What triggers the aggregation of wildtype proteins in sporadic disease? Is protein aggregation sufficient to drive pathology? 2) What drives the cell-specific vulnerabilities and variable clinical manifestation from ALS to FTD? 3) How do disease-associated alterations in protein homeostasis perturb communication in the tissue microenvironment? Given that more than 95% of ALS arises sporadically, and that the mechanisms of sporadic disease remain unknown, we will look beyond individual mutations, and establish a novel conceptual framework that examines the cellular changes that occur during disease states. We posit that by focusing on why TDP-43 aggregation occurs, especially in sporadic ALS, we will gain insights into pathogenic mechanisms underlying this spectrum of disorders. Our central hypothesis is that there are physical changes at the cell and tissue scale that initiate ALS/FTD. We propose that altered biophysical properties within cells (predominantly altered molecular crowding), which are linked to mechanical perturbations to the tissue microenvironment (stiffening, inflammation, edema causing osmotic stress), lead to age-dependent cellular dysfunction by altering the dynamics of assembly, disassembly and transport of macromolecular protein machines. We will test this hypothesis in cellular models, animal models, and patient tissue by (1) using novel tools to probe the intracellular biophysical environment of cells; (2) integrating these findings using novel genomics technologies applied to mouse models to study (i) how intracellular changes in crowding and extracellular changes in the tissue microenvironment may drive pathogenesis in vivo, and (ii) how such perturbations disrupt cell-cell communication in vulnerable regions of tissue; and (3) relating our findings to human disease by re-examining these findings in the context of a clinically and neuropathologically deeply curated cohort of ALS/FTD patients. These studies will allow us to address the following questions: 1) Why does abnormal protein aggregation and accumulation occur in sporadic disease, and how might this contribute to disease pathogenesis; 2) Do these alterations in protein homeostasis perturb intercellular communication in the tissue microenvironment; and 3) What drives the cell type vulnerability that makes ALS/FTD unique? The proposed work will accomplish the following: A) represent the first detailed survey of molecular crowding in neural cells; B) uncover whether a causal link between intracellular crowding, protein aggregation, and neurodegeneration exists, C) establish whether the impacts of intracellular crowding show cell type specific signatures including changes in protein- protein interactions, and D) provide a new framework to explore therapeutic strategies for treating ALS/FTD.

在零星营养性的侧索硬化症 - 佛罗内特痴呆（SALS/FTD）临床谱， 疾病相关蛋白（例如TDP-43）的聚集和积累是一种显着的神经病理学 Hallmark，但我们对为什么可能发生这一高度异常事件的原因一无所知。虽然多个中断 细胞过程与ALS有关，知识中仍然存在3个关键差距：1）触发的是什么 野生型蛋白在零星疾病中的聚集？蛋白质聚集足以驱动病理吗？ 2） 是什么驱动细胞特异性漏洞和从ALS到FTD的可变临床表现？ 3）如何 组织微环境中蛋白质稳态扰动通信的疾病相关改变？ 鉴于超过95％的ALS偶发出现，并且零星疾病的机制仍然存在 未知，我们将超越单个突变，并建立一个新颖的概念框架来检查 疾病状态期间发生的细胞变化。我们认为，通过关注TDP-43聚合的重点 发生，尤其是在零星的ALS中，我们将洞悉这一点的致病机制 疾病范围。我们的中心假设是细胞和组织存在物理变化 启动ALS/FTD的缩放。我们建议改变细胞内的生物物理特性（主要是 改变分子拥挤），与组织微环境的机械扰动有关 （僵硬，炎症，导致渗透应激的水肿），导致年龄依赖性细胞功能障碍 改变大分子蛋白质机器的组装，拆卸和运输的动力学。我们将 通过（1）使用新颖的工具探测该假设在细胞模型，动物模型和患者组织中 细胞内生物物理环境； （2）使用新型基因组技术整合这些发现 应用于小鼠模型来研究（i）在拥挤和细胞外变化的细胞内变化和细胞外变化 组织微环境可能会在体内驱动发病机理，（ii）这种扰动如何破坏细胞细胞 在脆弱的组织区域进行交流； （3）通过重新检查我们的发现与人类疾病有关 这些发现是在临床和神经病理学上策划的ALS/FTD患者队列的背景下。 这些研究将使我们能够解决以下问题：1）为什么异常蛋白质聚集 并积累出现在零星疾病中，这将如何促进疾病发病机理； 2）做 蛋白质稳态的这些改变在组织微环境中的细胞间通信； 3）是什么驱动使ALS/FTD与众不同的细胞类型漏洞？拟议的工作将完成 以下内容：a）表示神经细胞中分子拥挤的首次详细调查； b）发现是否a 存在细胞内拥挤，蛋白质聚集和神经退行性之间的因果关系，c）建立 细胞内拥挤的影响是否显示细胞类型特异性特异性特征，包括蛋白质的变化 蛋白质相互作用，d）提供了一个新框架，以探索治疗ALS/FTD的治疗策略。