Alex Li

Program: Molecular Genetics and Genomics

Current advisor: Fumihiko Urano, MD, PhD

Undergraduate university: Washington University, 2021

Enrollment year: 2023

Research summary
Investigating the impact of WFS1 mutations on β-cell stress responses using genome editing, proteomics, and functional assays to understand monogenic diabetes and guide therapeutic strategies.

My research centers on understanding how mutations in the Wolfram syndrome 1 (WFS1) gene contribute to β-cell dysfunction and the development of monogenic diabetes. WFS1 encodes an endoplasmic reticulum (ER)-resident protein involved in maintaining ER homeostasis, and its dysfunction has been implicated in ER stress, impaired insulin secretion, and eventual β-cell failure. Despite this, the precise molecular mechanisms linking WFS1 mutations to disease pathogenesis remain incompletely understood.

To address this, I use CRISPR-based genome editing to engineer human stem cell-derived β-cell models that carry clinically relevant WFS1 mutations. I then apply a combination of proteomic profiling, transcriptomic analysis, and functional assays (e.g., glucose-stimulated insulin secretion, ER stress response assays) to examine how these mutations alter cellular pathways. My goal is to identify how specific WFS1 variants impact β-cell identity, resilience to stress, and secretory function. And to also deivse a in-vitro as well as in-vivo plateform for applying Base editing techonology into treating and curing pathogenic missense mutation in wolfram syndrome.

Through this work, I aim to define the molecular underpinnings of WFS1-related β-cell dysfunction and to identify potential targets for therapeutic intervention. More broadly, this research contributes to our understanding of ER stress-related mechanisms in diabetes and supports the development of personalized approaches to treating monogenic forms of the disease.

Graduate publications
Yen A, Sarafinovska S, Chen X, Skinner DD, Leti F, Crosby M, Hoisington-Lopez J, Wu Y, Chen J, Li ZA, Noguchi KK, Mitra RD, Dougherty JD. 2024 MYT1L deficiency impairs excitatory neuron trajectory during cortical development. Nat Commun, 15(1):10308. PMCID: PMC11603064