Metabolic control of gut-brain axis in Familial Dysautonomia

项目摘要 这个项目的目标是确定新陈代谢和肠道微生物群是否构成 神经退行性疾病的显著特征是家族性自主神经障碍(FD)。在临床上 FD的特征涉及感觉和自主神经系统，包括心血管系统 不稳定和直立性低血压伴高血压发作，另一个主要特征是 胃肠道(GI)运动受损。人的胃肠道受到超过5亿人的调节 内源性神经元，称为肠道神经系统(ENS)。ENS是 自主神经系统，并已被证明在神经元数量严重减少 FD患者。此外，FD患者和FD小鼠模型体重不足，小鼠体重较低。 基本上没有皮下白色脂肪组织。其减少的根本原因是 质量尚不清楚，但最近的数据表明，线粒体功能在FD中受损 病人和老鼠。“心”和“脑”广泛交流，积累数据 展示肠道微生物群对新陈代谢和神经的强大作用 导致神经退行性疾病的恶化。我们假设FD 患者和小鼠体重不足是因为他们患有一种全球代谢综合征 肠道微生物群改变、能量平衡受损和线粒体 肠道功能障碍，以及肠道神经、自主神经和感觉神经系统的调节减少。 我们将采用多学科的方法，分析FD的肠道微生物组和代谢组 并在FD的小鼠模型中操纵这些系统以识别和分类原因 调节代谢损伤和神经元健康的机制。尽管具体来说 聚焦于FD，我们的结果将广泛适用于其他神经退行性疾病，其中 新陈代谢和微生物群被认为起到了作用。

Project Summary The goal of this project is to determine whether metabolism and the gut microbiome underlie hallmark features of the neurodegenerative disease, Familial Dysautonomia (FD). While clinical hallmarks of FD involve the sensory and autonomic nervous system, including cardiovascular instability and orthostatic hypotension with bouts of hypertension, another cardinal feature is impaired gastrointestinal (GI) tract motility. The human GI tract is regulated by over 500 million intrinsic neurons, called the Enteric Nervous system (ENS). The ENS is a component of the Autonomic Nervous System and has been shown to be severely reduced in neuronal number in FD patients. Furthermore, FD patients and mouse models for FD are underweight and mice are essentially devoid of subcutaneous white adipose tissue. The underlying etiology for their reduced mass is not known but recent data has shown that mitochondrial function is impaired in FD patients and mice. The “gut” and “brain” communicate extensively and accumulating data demonstrate the strong role the gut microbiome exerts on both metabolism and the nervous system, resulting in exacerbation of neurodegenerative disorders. We hypothesize that FD patients and mice are underweight because they suffer from a global metabolic syndrome induced by a combination of gut microbiome alteration, impaired energy homeostasis and mitochondrial dysfunction, and reduced gut regulation by the enteric, autonomic and sensory nervous systems. Using a multi-disciplinary approach, we will analyze the gut microbiome and metabolome of FD patients and manipulate these systems in mouse models of FD to identify and sort causal mechanisms mediating both metabolic impairments and neuronal health. Although specifically focused on FD, our results will broadly apply to other neurodegenerative diseases, where metabolism and the microbiome are thought to play a role.