Metabolic control of gut-brain axis in Familial Dysautonomia

家族性自主神经功能障碍肠脑轴的代谢控制

基本信息

批准号：
10163176
负责人：
VALERIE COPIE
金额：
$ 58.05万
依托单位：
MONTANA STATE UNIVERSITY - BOZEMAN
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10163176
关键词：
16S ribosomal RNA sequencing Adipose tissue Alzheimer&apos s Disease Autonomic nervous system Biological Models Blood Brain Cardiovascular system Clinical Collaborations Constipation Coupled Data Development Diarrhea Disease Disease model Dysautonomias Enteral Enteric Nervous System Epithelial Etiology Experimental Models Familial Dysautonomia Feces Feedback Functional disorder Gastric Emptying Gastrointestinal tract structure Genes Genetic Genetic Predisposition to Disease Genome Genotype Germ-Free Gluconeogenesis Gnotobiotic Goals Hand Health Hepatic Homeostasis Human Hypertension Impairment Individual Interdisciplinary Study Intervention Intestines Knockout Mice Knowledge Liquid Chromatography Liver Mass Spectrum Analysis Mediating Metabolic Metabolic Control Metabolic Pathway Metabolic dysfunction Metabolic syndrome Metabolism Mitochondria Motor Mus Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Neuropathy Nuclear Magnetic Resonance Orthostatic Hypotension Parkinson Disease Patients Phase Phenotype Play Regulation Research Resolution Role Sensory Solid Stress Structure System Testing Therapeutic Uses Underweight cell motility conditional knockout disease phenotype dysbiosis experimental study fecal transplantation gastrointestinal gastrointestinal epithelium gut microbiome gut-brain axis host microbiome innovation innovative technologies insight interdisciplinary approach loss of function mutation metabolome metabolomics microbiome microbiome alteration mitochondrial dysfunction motility disorder mouse model multidisciplinary nerve supply nervous system disorder neuron loss neuroregulation next generation novel phenome progressive neurodegeneration subcutaneous

项目摘要

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.

项目概要该项目的目标是确定新陈代谢和肠道微生物群是否是代谢的基础神经退行性疾病的标志性特征是家族性自主神经功能障碍（FD）。 FD 的特点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) 蠕动受损人类胃肠道受到超过 5 亿个细胞的调节。内在神经元，称为肠神经系统（ENS）。自主神经系统，已被证明神经数量严重减少此外，FD 患者和 FD 小鼠模型体重不足且小鼠体重不足。基本上缺乏皮下白色脂肪组织其减少的根本原因。质量未知，但最近的数据表明 FD 中线粒体功能受损患者和小鼠的“肠道”和“大脑”主要进行交流并积累数据。证明肠道微生物组对新陈代谢和神经系统发挥着重要作用系统，导致神经退行性疾病恶化。患者和小鼠体重不足，因为他们患有诱发的全身代谢综合征由肠道微生物组改变、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弱。我们将采用多学科方法分析 FD 的肠道微生物组和代谢组患者并在 FD 小鼠模型中操纵这些系统来识别和分类因果关系介导代谢损伤和神经健康的机制。专注于 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组被认为发挥了作用。