Metabolic control of gut-brain axis in Familial Dysautonomia

项目摘要 该项目的目标是确定代谢和肠道微生物组是否是 神经退行性疾病家族性自主神经功能障碍（FD）的标志性特征。虽然临床 FD的特征涉及感觉和自主神经系统，包括心血管 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）蠕动受损。人类的胃肠道受到超过5亿 肠神经系统（ENS）是一种神经系统，称为肠神经系统。ENS是 自主神经系统，并已被证明是严重减少神经元数量， FD患者。此外，FD患者和FD的小鼠模型体重过轻，并且小鼠体重较轻。 基本上没有皮下白色脂肪组织。其减少的潜在病因 质量尚不清楚，但最近的数据表明，FD患者的线粒体功能受损， 病人和老鼠“肠道”和“大脑”广泛交流，积累数据 证明肠道微生物组对新陈代谢和神经系统的强大作用。 系统，导致神经退行性疾病的恶化。我们假设FD 患者和小鼠体重过轻，因为它们患有诱导的全面代谢综合征， 肠道微生物组改变、能量稳态受损和线粒体 功能障碍，以及肠道、自主神经和感觉神经系统的肠道调节减少。 使用多学科方法，我们将分析FD的肠道微生物组和代谢组 病人和操作这些系统在小鼠模型的FD，以确定和排序因果 调节代谢损伤和神经元健康的机制。虽然具体来说 专注于FD，我们的结果将广泛适用于其他神经退行性疾病， 代谢和微生物组被认为发挥了作用。

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.