Effect of Combined Drug Therapy and Genetic Modifiers on Hepatosteatosis and Fibrosis in a Mouse Model for Alström Syndrome
Alström Syndrome (ALMS) is a genetic disorder characterized by obesity, progressive hearing and vision loss, and insulin resistance in humans. Variability of additional phenotypes exists among patients, often complicating diagnosis of ALMS (Marshall et al., 2011). Postmortem studies of patients with ALMS revealed severe fibrosis in multiple organs (Marshall et al., 2011). Currently, there are no known treatments for the fibrosis observed in ALMS patients. The purpose of the studies described herein was to examine the effects of losartan, an antifibrotic drug, on fibrogenesis and to identify genomic loci that modify ALMS phenotypes in a mouse model for ALMS (Alms1Gt/Gt).
A genome wide screen performed in two backcrosses to C57BL/6Ei and Balb/cJ mouse strains identified two genetic modifiers in Alms1Gt/Gt mice. A significant quantitative trait locus (QTL) for high density lipoproteins (HDL) was identified on chromosome 5 in the backcross to C57BL/6Ei while significant modifying loci for retinal degeneration was identified on chromosome 2 in the backcross to Balb/cJ. Further analysis with additional progeny may reveal other significant modifiers.
Histological and chemical analyses of samples from 24-week-old mutant and control mice treated with losartan were initiated in this study. The results of this study may help future therapeutic strategies for treating human patients with ALMS.
Hanusek, Ryan, "Effect of Combined Drug Therapy and Genetic Modifiers on Hepatosteatosis and Fibrosis in a Mouse Model for Alström Syndrome" (2012). Honors College. 53.