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W21-046: PPARαas metabolic target to restore intestinal permeability in an intestinal organoid model of feline diabetic enteropathy

Diabetes mellitus (DM) affects up to 70 cats per 10,000 in the U.S. DM is associated with defects in the intestinal barrier, commonly known as “leaky gut”. When damaged, the epithelial cell lining allows microbes to cross, increasing the risk for systemic infection and inflammation. In turn, inflammation further disrupts the intestinal barrier, leading to diarrhea and further translocation of microbes that can accelerate a ‘vicious cycle’. However, there remains a lack in understanding how epithelial cell junctions are regulated and which therapeutic targets will be effective. In a recently published study, we discovered a drug target, PPARα, that can reprogram cellular metabolism and restore intestinal barriers in non-human primates. Though the exact mechanism is still unclear, we also found that targeting PPARα using fenofibrate can reduce systemic inflammation and restore intestinal barriers in dogs with DM. Here we propose to investigate how to leverage a metabolic drug target for PPARα to restore intestinal barriers using a 3D-tissue model in a dish. Utilizing feline intestinal organoids developed in the Kol lab, we will establish a gut barrier dysfunction model ‘in-a-dish’, and determine whether fenofibrate can directly target intestinal inflammation or the underlying metabolic disease. This study highlights dual opportunities to advance veterinary research: 1) to identify novel mechanisms and drug targets to treat DM and 2) to develop a precise, non-invasive model for studying gastrointestinal disease in cats.

Grant ID: W21-046

Status: Active

Year Funded: 2021

Amount awarded: $29,530

Investigator: Amir Kol, DVM, Ph.D. ; University of California, Davis