Alex Li
Program: Molecular Genetics and Genomics
Current advisor: Fumihiko Urano, MD, PhD
Undergraduate university: Washington University
Research summary
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
Adamson SE, Li ZA, Hughes JW. 2023 Beta cell primary cilia mediate somatostatin responsiveness via SSTR3. Islets, 15(1):2252855.
Li ZA, Cho JH, Woodhams LG, Hughes JW. 2022 Fluorescence imaging of beta cell primary cilia. Front Endocrinol, 13():1004136.
Cho JH, Li ZA, Zhu L, Muegge BD, Roseman HF, Lee EY, Utterback T, Woodhams LG, Bayly PV, Hughes JW. 2022 Islet primary cilia motility controls insulin secretion. Sci Adv, 8(38)::eabq8486.
Djami-Tchatchou AT, Li ZA, Stodghill P, Filiatrault MJ, Kunkel BN. 2022 Identification of Indole-3-Acetic Acid-Regulated Genes in Pseudomonas syringae pv. tomato Strain DC3000. J Bacteriol, 204(1)::e0038021.