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.

Public Health Relevance

Novel clinical insight into neurodegenerative diseases is emerging from cutting-edge research on the gut-brain axis, or the cross-talk between the intestinal microbiome and neuronal function. This project leverages a unique multi-disciplinary research team and a highly interactive ?genome to phenome? approach, involving patients and murine models, to deconvolute systems-level complexities and define how the gut microbiome, the metabolome, and the enteric nervous system cooperatively regulate cardinal features of neurodegeneration. Our focus on neuropathy associated with Familial Dysautonomia will fill current clinical and basic knowledge gaps regarding this and other neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK117473-02
Application #
9787491
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Shea-Donohue, Terez
Project Start
2018-09-01
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Montana State University - Bozeman
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
625447982
City
Bozeman
State
MT
Country
United States
Zip Code
59717