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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.

依赖性神经退行性疾病，包括阿尔茨海默病、帕金森病和各种不太常见的疾病，影响大量的个人，并在很大程度上无法治疗。新的机制疾病代表了治疗开发未开发潜力。在这里，我们建议anastasis（来自希腊语， “死而复生”），或从终末半胱天冬酶激活中恢复，代表了诱导凋亡的新机制。年龄依赖性神经退行性疾病中的神经元死亡。我们提供的初步数据来自亚历山大病是一种典型的原发性星形胶质细胞介导的神经退行性疾病，这种融合会导致神经元死亡我们进一步利用了一个有价值的基因组规模的遗传筛选，在亚历山大病的体内果蝇模型中进行，以确定控制神经胶质愈合的机制和继发性非细胞自主神经变性。然后，我们测试的假设，anastasis有助于果蝇模型中的神经变性与阿尔茨海默氏症和相关疾病有关。最后我们检查tau蛋白病小鼠模型中与anastasis相关的标志物。我们的研究有可能定义一种新的机制，介导衰老相关疾病中的神经退行性变，开发减缓神经功能衰退的发作和进展的方法的机会。