Preclinical Testing of the Effects of Diet and FMRP on Gut and Brain Barrier Integrity in a Mouse Model of Fragile X
Abstract
The proposed research project addresses the Fiscal Year 2022 Peer Reviewed Medical Research Program Topic Areas of Fragile X Syndrome (FXS) and Nutrition Optimization. FXS is a developmental disability caused by a mutation in the FMR1 gene on the X-chromosome, which results in loss of expression of fragile X messenger ribonucleoprotein (FMRP). FMRP is a messenger RNA (mRNA) binding protein that plays pivotal roles in the transport, localization, and expression of hundreds of mRNAs. FXS is characterized by low IQ, autistic-like behavior, and seizures. A critical gap in medical care for persons with FXS is a viable, mechanistic-based therapy that translates between preclinical and clinical research. Recent literature indicates worse neurological and metabolic outcomes (seizures, autism, increased body weight) in mouse and/or human models of FXS as a function of diet. Thus, early-life exposures, such as diet, may exacerbate disease outcomes. This Department of Defense (DOD) Discovery Award application is innovative in proposing to test for an FMRP- and tight junction-mediated mechanism underlying gastrointestinal (GI) and brain barrier function in FXS model mice as well as testing for diet-induced effects on gut barrier integrity. The goal is to determine the effects of pro- and anti-convulsive diets, i.e., soy- and casein-based single-source diets, on gut barrier structure and function in wild-type and Fmr1KO littermate mice. The rationale is that loss of FMRP contributes to leaky gut syndrome through a tight junction-mediated mechanism affected by diet and that leaky gut contributes to brain dysfunction. This research has potential to provide a novel therapeutic target, tight junctions, and repurposing of experimental Celiac disease drugs that targe tight junctions for the treatment of FXS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310076
Entities
People
- Cara J Westmark
Organizations
- United States Army
- University of Wisconsin–Madison