Innovating high-resolution novel imaging approaches to elucidate mechanisms of prion-like spreadingof 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

基本信息

批准号：
10594409
负责人：
Aaron D. Gitler
金额：
$ 60.13万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10594409
关键词：
3-Dimensional Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amygdaloid structure Animals Area Brain Brain region Computer Models Corpus striatum structure Data Dementia Dementia with Lewy Bodies 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 pathology Location Maps Measures Methods Monitor Mus Nerve Degeneration Nervous System 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 Visualization alpha synuclein brain circuitry cell type cingulate cortex density empowerment experimental study fascinate functional decline genetic manipulation high resolution imaging imaging approach innovation insight interest neural novel olfactory bulb optogenetics pathology imaging prion-like protein aggregation tau Proteins therapeutic development tool

项目摘要

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中一个令人兴奋的新领域是神经退行性疾病蛋白的类朊病毒传播现象，朊病毒被认为是导致海绵状脑病的蛋白质感染因子，在这些罕见但痛苦的疾病中，朊病毒蛋白会转化。从正常的可溶形式到聚集的自我模板感染形式，这一过程会引发整个大脑的病理学和偶然的神经变性的不可阻挡的传播。帕金森病（PD）和阿尔茨海默病以及相关痴呆症等常见神经退行性疾病？如果是这样，它代表了理解疾病机制方面的游戏规则改变者，并为治疗开发开辟了许多新途径。然而，对类朊病毒的治疗或机制研究。传播需要开发强大的新成像方法来追踪类朊病毒的传播路径，并了解这些蛋白质聚集体在传播时如何改变大脑功能，我们需要了解为什么它们采取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，我们组建了一个由工程师和遗传学家组成的跨学科团队。首先，我们将使用最先进的大脑清理技术来获得。帕金森病蛋白 α-突触核蛋白的类朊病毒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。传播将使我们能够识别与传播路径相关的基因表达模式，并提名基因进行功能研究，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）来揭示传播的纵向效应。大脑网络活动中的朊病毒样传播同样，神经活动对朊病毒传播的影响将提供对神经退行性疾病的朊病毒传播的基本机制的了解，我们应用的工具和我们学到的经验教训可能会广泛适用于包括阿尔茨海默病和相关疾病的神经退行性疾病。痴呆症。