Interplay of the microbiome and the brain in neurodegenerative disease

描述(由申请人提供)：最近科学研究中最出人意料和令人惊讶的领域之一是肠道微生物群对健康和疾病的相互作用。有趣的发现包括微生物组对心脏病的影响，因为肉类消费促进了细菌菌群产生的代谢物，以及微生物组对肥胖的影响。微生物群与宿主之间的相互作用可能是双向的，宿主状态影响肠道微生物群的多样性和范围，肠道微生物群影响宿主健康和疾病状态。了解这些相互作用以及它们如何影响疾病和受疾病影响是生物学的一个爆炸性领域，对健康具有深远的影响。然而，这项工作中的一个巨大挑战是在人类或小鼠等哺乳动物模型上进行实验的难度和费用。疾病，特别是慢性神经退行性疾病，由于个体的高龄和身体状况，尤其难以研究这些相互作用。我们建议使用果蝇进行开创性研究，以评估微生物组是否受到动物退行性疾病的影响，以及微生物组是否影响疾病的表现。我们的实验室特别关注肌萎缩侧索硬化症/额颞叶痴呆和帕金森氏病，我们建议启动针对这些疾病的强大模型的研究。在目标1中，我们将评估神经退行性疾病对动物微生物区系的影响。我们将使用一系列针对这些疾病的关键模型，从纵向上定义动物肠道微生物群在成人疾病发展过程中的作用。这些研究将确定微生物组在疾病发生或发展时是否发生变化，并提供不同疾病模型之间这种影响的比较。在目标2中，我们将研究这种相互作用，以确定肠道微生物是否影响神经退行性疾病的进展和严重程度。我们将在无菌培养基上培养无菌疾病模型，并评估疾病表型的关键基准和特征。这些实验将确定动物的肠道微生物区系本身是否对疾病的发生、进展或严重程度产生影响。在这里，我们利用了这样一个事实，即用寄生苍蝇进行实验是直接的，而用寄生脊椎动物进行实验是相当困难和昂贵的。这些目标的发现将定义微生物群和动物神经退行性疾病状态之间的相互影响，以评估这些相互关联的联系。这些研究将为神经退行性疾病中微生物与动物的相互作用建立一个“简单的模型”基础，为更复杂但速度更慢、成本更高的动物提供预测。

DESCRIPTION (provided by applicant): One of most unexpected and surprising recent areas of scientific investigation are interactions of the intestinal microbiome on health and disease. Interesting findings include the impact of the microbiome on heart disease due to metabolites generated by bacterial flora promoted by meat consumption, and the impact of the microbiome on obesity. The interactions between the microbiome and the host are likely bidirectional, with the host state impacting the diversity and range of the intestinal microbiome, as well as the intestinal microbiome impacting host health and disease state. Understanding these interactions and how they influence and are influenced by disease is an exploding area of biology with profound implications for health. However, a huge challenge in this work is the difficulty and expense in performing the experiments, in either humans or mammalian models like mice. Diseases, especially chronic neurodegenerative diseases, are especially difficult to investigate for these interactions because of the advanced age of the individuals and their physical condition. We propose to use Drosophila for pioneering studies to assess if the microbiome is impacted by degenerative disease in the animal, and if the microbiome impacts the presentation of disease. Our laboratory has a special focus on amyotrophic lateral sclerosis/frontotemporal dementia and Parkinson's disease, and we propose to initiate studies with robust models for these disorders. In Aim 1, we will assess the impact of neurodegenerative disease on the microbiota of the animal. We will define the gut microbiome of animals over progression of disease longitudinally in the adult, using a range of critical models for these diseases. These studies will define if the microbiome is altered upon disease onset or progression, as well as provide a comparison of this impact between different models of disease. In Aim 2, we will investigate the reciprocal interaction, to determine if the gut microbiome impacts progression and severity of neurodegenerative disease. We will grow disease models germ free on axenic medium and assess key benchmarks and features of the disease phenotype. These experiments will define whether the gut microbiota of the animal itself has an impact on the onset, progression or severity of disease. Here we take advantage of the fact that experiments with gnotobiotic flies are straightforward, while experiments with gnotobiotic vertebrates are quite difficult and expensive. The findings of these Aims will define the reciprocal impact between the microbiome and the neurodegenerative disease state of the animal, to assess these inter-related connections. These studies will establish a "simple model" foundation for microbiota-animal interactions in neurodegenerative disease, providing predictions for more complex-but slower and far more expensive-animals.