Poster #046, City of Hope
Effect of β-Cell-Specific Rank/Lgr4 Double Knockout on β-Cell Maturation and Insulitis in Aged Mice
Mentors: Joanna Filipowska, PhD and Zelda Cisneros, BS; PI: Rupangi Vasavada, PhD
Aging is a diabetes-associated stressor that impairs pancreatic β-cell health. Receptor Activator of Nuclear Factor kappa-B (RANK) and Leucine-rich Repeat-containing G-protein coupled Receptor (LGR4), regulate β-cell fitness negatively and positively, respectively. β-cell-specific Lgr4 knockout (LGR4-KO) compromises β-cell fitness, whereas additional Rank deletion rescues it under basal conditions. Furthermore, aged female LGR4-KOs showed impaired β-cell identity and increased islet inflammation (insulitis), a hallmark of type 1 diabetes. We aim to determine whether β-cell-specific Rank/Lgr4 double knockout (DKO) normalizes the β-cell maturation and insulitis phenotypes observed in aged LGR4-KO mice. Pancreatic sections from aged wild-type (WT), LGR4-KO, and DKO mice were stained via immunofluorescence for insulin and β-cell maturation marker Urocortin-3 (UCN3). Insulitis was scored based on hematoxylin and eosin staining. We predict that compared to LGR-KO, DKO mice will normalize UCN3 expression and insulitis to WT levels. Our findings could identify mechanisms and therapeutic targets for preserving β-cell health during aging.