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.

概括全世界有超过5500万人患有痴呆症，预计这一数字将达到7800万根据世界卫生组织的预测，2030年。痴呆症的主要原因是阿尔茨海默氏症疾病（AD），其区分分子特征是淀粉样蛋白B（AB）斑块的存在，异常存在大脑中的磷酸化tau。高磷酸化tau的聚集体作为神经纤维缠结（NFT） AD和大约20种其他神经退行性疾病统称为tauopathies。值得注意的是除了AD，Tauopathies没有明显的AB积累，这表明Tau在神经变性。基于小鼠模型的许多研究支持了这一概念。但是， Tau发病机理的确切性质仍然难以捉摸，因此阻碍了有效的药物发展。剖析热磷酸化的tau介导的神经变性的机械细节，并利用果蝇果蝇（Drosophila Melanogaster 食物）阿尔茨海默氏病和陶氏病的模型。该模型使我们能够在成人苍蝇，并精确地定义了生物体暴露于生物的p-tau/tau的形式，这两个都不是可能使用转基因飞行模型。通过将成年果蝇用热磷酸化的tau喂养，我们有蝇中AD的概括神经功能特征，包括晚期和年龄依赖性神经变性，血脑屏障分解，大脑不同区域的明显病理。这些病理特征在治疗后不到四周内成为证据，因此提供了比其他几个月发展神经病理学的动物模型的重要优势。我们研究的总体目标是使用这种新颖的飞行模型来帮助开发有效的手段广告疗法和预防。为此，我们将使用此探索性R21项目来表征疾病状态该模型并为未来的综合机械研究奠定了基础，以了解肠脑神经退行性疾病和药物发现项目中的信号传导。我们将使用各种方法了解高磷酸化tau损坏的分子基础，并检查相互作用在P-TAU和已知和可疑的AD贡献者之间，例如AB，载脂蛋白E（APOE）和A-核蛋白。