Anastasis in age-related neurodegeneration

年龄相关神经变性的分析

基本信息

批准号：
10590214
负责人：
MEL B FEANY
金额：
$ 26.85万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10590214
关键词：
Address Adult Affect Age Aging Alexander Disease Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Animal Model Astrocytes Biochemical Brain Stem Caspase Cell Culture Techniques Cell Death Cells Cessation of life Clinical Data Development Disease Disease Progression Drosophila genus Genes Genetic Genetic Screening Glial Fibrillary Acidic Protein Gliosis Greek Individual Inflammatory Inhibition of Apoptosis Injury Intermediate Filament Proteins Knowledge Longevity Mammalian Cell Mammals Mediating Modeling Morphology Mus Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Neuroglia Neurologic Neurons Parkinson Disease Pathologic Pathway interactions Play Process Rattus Recovery Role Source Specificity Spinal Cord Syndrome System Tauopathies Testing Tissues Toxic effect Transgenic Mice Work age related age related neurodegeneration aging brain cytokine design dysmyelination effective therapy fly genetic analysis genome-wide human stem cells in vivo infancy mouse model nervous system disorder neuron loss neurotoxicity novel protein aggregation stem cell model tau Proteins therapy development

项目摘要

Age-dependent neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and a variety of less common disorders, affect large numbers of individuals and are largely untreatable. Novel mechanisms of disease represent untapped potential for therapy development. Here we propose that anastasis (from the Greek, “rising from the dead”), or recovery from terminal caspase activation, represents a new mechanism inducing neuronal death in age-dependent neurodegenerative diseases. We present preliminary data derived from models of Alexander disease, an exemplar primary astrocyte mediated neurodegenerative disorder, to suggest that that anastasis drives neuronal death. We further capitalize on a valuable genome-scale genetic screen performed in an in vivo Drosophila model of Alexander disease to define mechanisms controlling glial anastasis and secondary non-cell autonomous neurodegeneration. We then test the hypothesis that anastasis contributes to neurodegeneration in Drosophila models of relevant to Alzheimer’s disease and related disorders. Finally, we examine mouse models of tauopathy for markers associated with anastasis. Our studies have the potential to define a new mechanism mediating neurodegeneration in aging-related disorders with accompanying opportunities for development of approaches to slow the onset and progression of neurological decline.

年龄依赖性神经退行性疾病，包括阿尔茨海默氏病，帕金森氏病和多种在较不常见的疾病中，影响大量个体，并且在很大程度上无法治疗。新颖的机制疾病代表了尚未开发的治疗发展潜力。在这里，我们提出了Anastasis（来自希腊人， “从死者上升”）或从终端caspase激活中恢复，代表了一种新的机制依赖年龄的神经退行性疾病的神经元死亡。我们介绍从亚历山大病的模型，一种典范的原发性星形胶质细胞介导的神经退行性疾病，提示 anastasis驱动了神经元死亡。我们进一步利用有价值的基因组规模遗传筛选在亚历山大疾病的体内果蝇模型中进行的，以定义控制神经胶质的机制和次要非细胞自主神经退行性变性。然后，我们检验了anastasis贡献的假设与与阿尔茨海默氏病和相关疾病相关的果蝇模型中的神经变性。最后，我们检查tauopathy的小鼠模型与厌氧症相关的标记。我们的研究有可能定义一种新的机制，介导与衰老相关的疾病中的神经退行性关系开发方法的机会，以减缓神经系统衰落的发作和发展。