Innovating high-resolution novel imaging approaches to elucidate mechanisms of prion-like spreading of neurodegenerative disease

创新高分辨率新型成像方法来阐明神经退行性疾病的朊病毒样传播机制

• 批准号: 9974219
• 负责人: Aaron D. Gitler
• 金额: $ 60.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9974219
• 关键词: 3-Dimensional; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amygdaloid structure; Animals; Area; Brain; Brain region; Computer Models; Corpus striatum structure; Data; Dementia; Development; Diffusion; Disease; Distal; Encephalopathies; Engineering; Functional Magnetic Resonance Imaging; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Predisposition to Disease; Goals; Image; Infectious Agent; Injections; Investigation; LRRK2 gene; Laboratories; Learning; Lewy Body Dementia; Lewy body pathology; Location; Maps; Measures; Methods; Monitor; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Pattern; Predisposition; Prion Diseases; Prions; Process; Proteins; Research; Resolution; Rodent; Role; Route; Substantia nigra structure; Synapses; Technology; Testing; Therapeutic; Time; alpha synuclein; base; brain circuitry; cell type; cingulate cortex; density; experimental study; fascinate; functional decline; high resolution imaging; imaging approach; innovation; insight; interest; novel; olfactory bulb; optogenetics; pathology imaging; prion-like; protein aggregation; relating to nervous system; synuclein; tau Proteins; therapeutic development; tool

An exciting new area in neurodegenerative disease research is the emerging phenomenon of prion-like spreading of neurodegenerative disease proteins. Prions are well established as the protein-based infectious agent underlying the spongioform encephalopathies. In these rare, albeit devastating, diseases the prion protein converts from the normal soluble form to the aggregated self-templating infectious form. This process initiates an inexorable spread of pathology and contingent neurodegeneration throughout the brain. But could this disease mechanism extend to the more common neurodegenerative diseases like Parkinson’s disease (PD) and Alzheimer’s disease and related dementia? If so, it represents a game changer in terms of understanding disease mechanisms and opens many new avenues for therapeutic development. However, any therapeutic or mechanistic investigation into prion-like spreading will require the development of powerful new imaging approaches to track the path of prion-like spread and understand how these protein aggregates alter brain function as they spread. We will need to understand why they take some routes but not others and how this impacts brain function. To address this challenge, we have formed an interdisciplinary team, consisting of an engineer and a geneticist. First, we will use state of the art brain clearing technology to obtain high-resolution images of prion-like protein propagation of the Parkinson’s disease protein α-synuclein. We will monitor these aggregates as they spread from one neuron to the next, tracking their paths. These high-resolution brain wide 3D maps of alpha-synuclein spreading will empower us to identify gene expression patterns associated with spreading paths and to nominate genes for functional studies. Then, we will utilize advanced high-resolution optogenetic functional magnetic resonance imaging (ofMRI) to reveal the longitudinal effects of prion-like spreading on brain network activity and likewise the impact of neural activity on prion-like spreading. Our experiments will provide fundamental mechanistic insight into prion-like spread of neurodegenerative disease. The tools we apply and the lessons we learn will likely be broadly applicable to neurodegenerative diseases including Alzheimer’s disease and related dementias.

神经退行性疾病研究的一个令人兴奋的新领域是神经退行性疾病蛋白质的朊病毒样扩散的新现象。朊病毒被公认为海绵状脑病的蛋白质基础的感染剂。在这些罕见的疾病中，尽管是毁灭性的，朊病毒蛋白从正常的可溶形式转化为聚集的自模板感染形式。这个过程引发了一个不可阻挡的传播病理和偶然的神经变性整个大脑。但这种疾病机制是否可以扩展到 常见的神经退行性疾病，如帕金森病（PD）和阿尔茨海默病及相关痴呆症？如果是这样的话，它代表了理解疾病机制的游戏规则改变者，并为治疗开发开辟了许多新途径。然而，对朊病毒样扩散的任何治疗或机制研究都需要开发强大的新成像方法来跟踪朊病毒样扩散的路径，并了解这些蛋白质聚集体在扩散时如何改变大脑功能。我们需要了解为什么它们选择某些路线而不是其他路线，以及这如何影响大脑功能。为了应对这一挑战，我们组建了一个跨学科团队，由一名工程师和一名遗传学家组成。首先，我们将使用最先进的大脑净化技术， 帕金森病蛋白α-突触核蛋白的朊病毒样蛋白传播的高分辨率图像。我们将监测这些聚集体从一个神经元传播到下一个神经元的过程，跟踪它们的路径。这些高分辨率的α-突触核蛋白扩散的全脑3D图谱将使我们能够识别与扩散路径相关的基因表达模式，并为功能研究提名基因。然后，我们将利用先进的高分辨率光遗传学功能磁共振成像（ofMRI）来揭示朊病毒样扩散对大脑网络活动的纵向影响， 神经活动对朊病毒样扩散的影响也是如此。我们的实验将为神经退行性疾病的朊病毒样传播提供基本的机制见解。我们应用的工具和我们学到的教训可能会广泛适用于神经退行性疾病，包括阿尔茨海默病和相关痴呆症。