A novel non-transgenic fly model for tauopathies

一种新型非转基因 tau蛋白病果蝇模型

基本信息

批准号：
10662019
负责人：
Min-Hao Kuo
金额：
$ 23.48万
依托单位：
MICHIGAN STATE 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：
2023-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662019
关键词：
Adult Aftercare Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapy Amyloid beta-Protein Animal Model Animals Apolipoprotein E Area Behavior Blood - brain barrier anatomy Brain Categories Clinical Cognition Complement Defect Dementia Deposition Development Disease Drosophila genus Drosophila melanogaster Drug Modelings Exposure to Food Food Supplements Foundations Functional disorder Future Genes Genetic Genetic Techniques Goals Human Impaired cognition Injections Knock-in Locomotion Modeling Molecular Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurologic Organism Pathogenesis Pathogenicity Pathologic Pathology Patients Persons Phosphorylation Phosphotransferases Play Predisposing Factor Prevention Protein Isoforms Proteins Proteolysis Reporting Research Risk Factors Role Sampling Senile Plaques Symptoms System Tauopathies Therapeutic Transgenic Animals Transgenic Organisms Translational Research World Health Organization abeta accumulation abnormally phosphorylated tau age related alpha synuclein antagonist blood damage brain tissue drug development drug discovery epidemiology study expectation feeding fly gut-brain axis hyperphosphorylated tau mouse model mutant neurological pathology neurotoxic novel recruit synergism tau Proteins tau mutation tau-1 tool trait transgene expression

项目摘要

SUMMARY Over 55 million people live with dementia worldwide, and this number is expected to reach 78 million by 2030, according to the projection by the World Health Organization. The main cause of dementia is Alzheimer’s disease (AD), whose distinguishing molecular feature is the presence of amyloid b (Ab) plaques, and abnormally phosphorylated tau in brain. Aggregates of hyperphosphorylated tau as neurofibrillary tangles (NFT) are seen in AD and about 20 other neurodegenerative disorders collectively known as tauopathies. It is noteworthy that except AD, tauopathies do not have significant Ab accumulation, suggesting a key causal role of tau in neurodegeneration. This notion has been supported by many studies based on mouse models. However, the exact nature of tau pathogenesis remains elusive, therefore hampering effective drug development. To dissect the mechanistic details of hyperphosphorylated tau-mediated neurodegeneration, and to take advantage of the advanced genetic tools offered by the fruit fly Drosophila melanogaster, we have established a novel in cibo (in food) model of Alzheimer’s disease and tauopathies. This model gives us the ability to induce the disease in adult flies, and precisely define the form of p-tau/tau that the organism is exposed to, both of which are not possible using a transgenic fly model. By feeding adult Drosophila with hyperphosphorylated tau, we have recapitulated critical neurological features of AD in flies, including the late onset and age-dependent neurodegeneration, disintegrated blood brain barrier, and conspicuous pathology in different areas of the brain. These pathological traits become evident in less than four weeks after the treatment, therefore providing a significant advantage over other animal models that take months to develop neurological pathology. The overarching goal of our research is to use this novel fly model to help develop efficacious means for AD therapy and prevention. To this end, we will use this exploratory R21 project to characterize the disease state of this model and lay the foundation for future comprehensive mechanistic studies to understand gut-brain signaling in neurodegenerative diseases, and drug discovery projects. We will use a variety of approaches to understand the molecular basis for hyperphosphorylated tau-inflicted pathology, and examine the interplay between p-tau and known and suspected AD contributors such as Ab, apolipoprotein E (APOE), and a-synuclein.

概括全球有超过 5500 万人患有痴呆症，预计到 2020 年这一数字将达到 7800 万据世界卫生组织预测，到2030年，痴呆症的主要原因是阿尔茨海默氏症。疾病 (AD)，其显着的分子特征是淀粉样蛋白 b (Ab) 斑块的存在，并且异常大脑中磷酸化的 tau 蛋白以神经原纤维缠结 (NFT) 的形式出现。 AD 和大约 20 种其他神经退行性疾病统称为 tau 病。除 AD 外，tau 蛋白病没有显着的 Ab 积累，这表明 tau 蛋白在 AD 中起着关键的因果作用。许多基于小鼠模型的研究都支持这一观点。 tau 发病机制的确切性质仍然难以捉摸，因此阻碍了有效的药物开发。过度磷酸化 tau 介导的神经变性的机制细节，并利用果蝇 Drosophila melanogaster 提供的先进遗传工具，我们在 cibo (in 食物）阿尔茨海默氏病和 tau蛋白病模型，该模型使我们能够诱发这种疾病。成年果蝇，并精确定义生物体所接触的 p-tau/tau 形式，这两种形式都不是通过用过度磷酸化的 tau 蛋白喂养成年果蝇，我们可以实现这一目标。概括了果蝇 AD 的关键神经学特征，包括迟发性和年龄依赖性神经退行性变、血脑屏障瓦解以及大脑不同区域出现明显的病理变化。这些病理特征在治疗后不到四个星期内变得明显，因此提供了与其他需要数月才能形成神经病理学的动物模型相比，具有显着优势。我们研究的总体目标是利用这种新颖的苍蝇模型来帮助开发有效的方法为此，我们将使用这个探索性 R21 项目来描述疾病状态。该模型的建立，为未来理解肠脑的综合机制研究奠定了基础我们将使用多种方法来研究神经退行性疾病中的信号传导和药物发现项目。了解过度磷酸化 tau 引起的病理学的分子基础，并检查相互作用 p-tau 与已知和可疑的 AD 贡献者（如 Ab、载脂蛋白 E (APOE) 和 a-突触核蛋白）之间的关系。