Project Details

Investigating the role of PPAR-α in rescuing Microvillus Inclusion Disease

Casey Johnson, MD

Summary

BACKGROUND: Microvillus Inclusion Disease (MVID) is a rare, infantile-onset enteropathy caused by biallelic MYO5B mutations, leading to severe epithelial polarity defects, intractable diarrhea, and lifelong parenteral nutrition dependency with no targeted therapies available. Our lab recently demonstrated that γ-secretase inhibition with DAPT partially restores epithelial structure and function in patient-derived MVID enteroids, with RNA sequencing revealing that rescued genes are enriched for PPARα signaling pathways. Supporting this mechanism, MVID enteroids exhibit cholesterol accumulation and NPC1L1 mislocalization, while PPARα activation with WY-14643 partially restores polarity markers. GAP: While γ-secretase inhibition reverses key MVID features, its mechanism—and the specific role of PPAR-α—remains unclear. Determining whether PPAR-α activation is necessary or sufficient for recovery is critical for therapeutic development. HYPOTHESIS:(1) MYO5B loss-of-function disrupts membrane lipid composition and trafficking, impairing epithelial function, while γ-secretase inhibition restores these processes. (2) PPARα activation mediates the rescue effect of γ-secretase inhibition, restoring epithelial structure and function in MYO5B-deficient cells. METHODS: Using MVID and control enteroids, we will assess lipid content and trafficking via FACS and confocal imaging, and evaluate rescue using electrophysiology and alkaline phosphatase activity. We will test DAPT and PPARα modulators, including FDA-approved fibrates and novel research compounds. RESULTS: Pending. IMPACT: This study will clarify the role of lipid homeostasis in epithelial function and may support the development of the first targeted therapy for MVID.