Interplay of the microbiome and the brain in neurodegenerative disease

微生物组和大脑在神经退行性疾病中的相互作用

• 批准号: 8755389
• 负责人: Nancy M Bonini
• 金额: $ 23.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755389
• 关键词: Adult; Affect; Age; Amyotrophic Lateral Sclerosis; Animal Diseases; Animal Model; Animals; Area; Benchmarking; Biology; Brain; Brain Diseases; Chronic; Complex; Consumption; Degenerative Disorder; Disease; Disease Progression; Disease model; Drosophila genus; Elderly; Foundations; Frontotemporal Dementia; Future; Genetic; Germ-Free; Gnotobiotic; Health; Heart Diseases; Human; Individual; Intestines; Investigation; Laboratories; Laboratory Animal Production and Facilities; Lead; Mammals; Meat; Modeling; Mus; Neurodegenerative Disorders; Obesity; Onset of illness; Parkinson Disease; Probiotics; Risk Factors; Severities; Severity of illness; Specific qualifier value; Study models; System; Therapeutic; Transgenes; Up-Regulation; Vertebrates; Work; disease phenotype; fly; gut microbiota; human disease; insight; interest; loss of function; microbial; microbiome; novel; physical conditioning; public health relevance; research study

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.

描述（由申请人提供）：科学研究的最出乎意料和最令人惊讶的领域之一是肠道微生物组在健康和疾病上的相互作用。有趣的发现包括微生物组对由肉类消耗促进的细菌菌群产生的代谢产生的代谢产生的心脏病的影响，以及微生物组对肥胖症的影响。微生物组与宿主之间的相互作用可能是双向的，宿主状态会影响肠道微生物组的多样性和范围，以及影响宿主健康和疾病状态的肠道微生物组。了解这些相互作用及其如何影响和受疾病影响是生物学的爆炸领域，对健康产生了深远的影响。但是，这项工作的巨大挑战是在人类或小鼠（如小鼠）中执行实验的困难和费用。由于个体的高龄及其身体状况，疾病，尤其是慢性神经退行性疾病，很难研究这些相互作用。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动物退化性疾病的影响，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性的侧面硬化症/额颞痴呆和帕金森氏病，我们建议对这些疾病进行健壮模型进行研究。在AIM 1中，我们将评估神经退行性疾病对动物菌群的影响。我们将使用这些疾病的一系列关键模型来定义动物的肠道微生物组，而不是成年人的疾病进展。这些研究将定义微生物组是否随着疾病的发作或进展而改变，并提供了不同疾病模型之间的影响的比较。在AIM 2中，我们将研究相互的相互作用，以确定肠道微生物组是否影响神经退行性疾病的进展和严重程度。我们将在轴承培养基上种植疾病模型，并评估疾病表型的关键基准和特征。这些实验将定义动物本身的肠道菌群是否会影响疾病的发作，进展或严重程度。在这里，我们利用了gnotobiotic果蝇的实验很简单的事实，而gnotobiotic脊椎动物的实验非常困难和昂贵。这些目标的发现将定义微生物组和动物神经退行性疾病状态之间的相互影响，以评估这些相关的连接。这些研究将为神经退行性疾病中的微生物群 - 动物相互作用建立一个“简单模型”基础，为更复杂但更昂贵的动脉症提供了预测。