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Systems-Level Approach to Neuronopathic Lysosomal Storage Disorders

神经病性溶酶体贮积症的系统级方法

基本信息

批准号：
10721768
负责人：
JONATHAN D COOPER
金额：
$ 160.46万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10721768
关键词：
Affect Applications Grants Artificial Intelligence Astrocytes Atlases Automobile Driving Behavioral Biochemical Biochemical Pathway Biogenesis Biology Brain CLN2 gene Candidate Disease Gene Catalogs Cell Nucleus Cells Cellular Metabolic Process Cellular Stress Central Nervous System Central Nervous System Diseases Cessation of life Communication Complex Data Disease Disease Progression Disease model Effector Cell Enzymes Foundations Functional disorder Future Genes Genetic Genetic Transcription Goals Growth Health Human Individual Induced pluripotent stem cell derived neurons Interphase Cell Investigation Knowledge Link Lipids Lysosomes Macrophage Mediating Membrane Metabolic Metabolic Pathway Methodology Microglia Mucopolysaccharidosis III B Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Organ Outcome Output Pathogenesis Pathogenicity Pathologic Pathway Analysis Pathway interactions Patients Phenotype Post-Translational Protein Processing Proteins Proteomics Recycling Regulation Role Route Signal Pathway Signal Transduction Site Stress System Systems Biology Systems Integration Test Result Testing Therapeutic Tissues Training Transgenic Mice Translational Research Work brain health candidate identification cell type cellular pathology combat disease phenotype enzyme deficiency exhaust human model individual response innovation knowledge of results lipidomics lysosomal proteins metabolomics mouse model novel novel therapeutics premature prevent protein protein interaction response therapeutic development therapeutic target tool transcription factor

项目摘要

Neuronopathic lysosomal storage disorders (LSDs) are a group of fatal neurodegenerative diseases caused by genetic defects in components of the lysosome, which is the major site within the cell for the degradation and recycling of exhausted cellular components. Defective lysosomes accumulate undegraded storage material, which has classically been thought to be toxic for the cell and the driver of the pathogenic cascade of the dis- ease. Recent advances in the investigation of the lysosome, however, have shown that the storage burden it- self can be uncoupled from the most dramatic effects of the disease on the affected organs. Moreover, there are emerging roles of the lysosome as a central player in the regulation of cell metabolism which are distinct from its classical role as a cellular degradation site. The central hypothesis of this proposal is that are the changes in the communication between the lysosome and the rest of the cell, rather than the storage itself, that drive disease pathogenesis. Determining exactly which components of the lysosomal communication network mediate disease propagation, in which cell type, and how, is important because it could unveil the next generation of therapeutic targets. We propose to use innovative genetic tools and artificial intelligence-driven analytical pipelines to mechanistically investigate changes in lysosomal content and communication in the central nervous system of mouse models of two distinct LSDs. In Aim 1 we will catalogue LSD-associated changes in lysosomal content and composition and determine their relationship with LSD-specific cellular features based on the perturbation of components of the broad lysosomal gene metabolic network. In Aim 2 we will investigate the changes in the signaling network that mediates communication of the lysosome with the nucleus and determine the effectors of the cell’s response to lysosomal stress. In Aim 3 we will place the study of lysosomal content, signaling, and dysfunction in the context of specific cell types (neurons, astroglia, macrophages) to determine their role in the initiation and propagation of disease. Results from this study will provide the first atlas of changes in lysosomal content and signaling components in LSDs and will pioneer the integrative study of the lysosome as a multi-level network of causally associated components and pathways. Knowledge resulting from this study could lay the foundation for future translational investigation of treatments for neuronopathic LSDs.

神经元病性溶酶体贮积症（Neuronopathic lysosomal storage disorders，LSD）是由溶酶体组分的遗传缺陷引起的一组致命的神经退行性疾病，溶酶体是细胞内用于降解和回收耗尽的细胞组分的主要位点。有缺陷的溶酶体积累未降解的储存物质，其通常被认为对细胞有毒，并且是疾病的致病级联的驱动因素。然而，对溶酶体研究的最新进展表明，储存负担本身可以与疾病对受影响器官的最显著影响脱钩。此外，溶酶体作为细胞代谢调节中的核心参与者的新角色与其作为细胞降解位点的经典角色不同。该提议的中心假设是，驱动疾病发病机制的是溶酶体与细胞其余部分之间的通信变化，而不是存储本身。准确确定溶酶体通讯网络的哪些组分介导疾病传播，在哪种细胞类型中以及如何介导疾病传播非常重要，因为它可以揭示下一代治疗靶点。我们建议使用创新的遗传工具和人工智能驱动的分析管道来机械地研究两种不同LSD小鼠模型中枢神经系统中溶酶体含量和通信的变化。在目标1中，我们将对LSD相关的溶酶体含量和组成变化进行分类，并根据广泛的溶酶体基因代谢网络组分的扰动确定它们与LSD特异性细胞特征的关系。在目标2中，我们将研究介导溶酶体与细胞核通讯的信号网络的变化，并确定细胞对溶酶体应激反应的效应物。在目标3中，我们将在特定细胞类型（神经元，星形胶质细胞，巨噬细胞）的背景下研究溶酶体含量，信号传导和功能障碍，以确定它们在疾病发生和传播中的作用。这项研究的结果将提供LSDs中溶酶体含量和信号成分变化的第一个图谱，并将开创溶酶体作为因果相关成分和途径的多层次网络的综合研究。从这项研究中获得的知识可以为未来神经病性LSD治疗的转化研究奠定基础。