Poster abstracts
Poster number 23 submitted by Geremy Lerma
Modifying Duchenne muscular dystrophy severity in zebrafish by regulating Tgfβ
Geremy T. Lerma (Ohio State University), Natalie M. Aloi (Ohio State University), Joseph C. Beljan (Ohio State University), Jared C. Talbot (Ohio State University)
Abstract:
Duchenne Muscular Dystrophy (DMD) is a dystrophinopathy characterized by progressive muscle degeneration and weakness that affects approximately 1 in 3500 live male births. Despite development of promising therapeutics, there is currently no cure. Transforming Growth Factor β (TGFβ) is a multifunctional cytokine that is aberrantly activated in muscular dystrophies, including DMD. TGFβ exacerbates disease progression by promoting inflammation and fibrosis in muscle with chronic injury. Genome-wide association studies identified variant alleles of TGFβ regulatory proteins which corresponded with age to loss of ambulation in DMD patients. These proteins are Latent TGFβ Binding Protein 4 (LTBP4), a protein responsible for TGFβ secretion and deposition into the extracellular matrix (ECM), and Thrombospondin 1 (THBS1), a protein responsible for activation of TGFβ in the ECM. Protective LTBP4 and THBS1 alleles result in reduced TGFβ signaling while risk alleles cause the opposite. We are utilizing chemical and genetic approaches in the zebrafish DMD (dmd) disease model to investigate how TGFβ (Tgfβ) signaling influences the dmd phenotype. Transient inhibition of Tgfβ receptors before significant muscle degeneration begins results in significant and sustained rescue of dmd mutant muscle integrity and ultrastructure at later stages when untreated controls show severe damage. We have generated and are characterizing loss-of-function alleles of ltbp4, thbs1a, and thbs1b (zebrafish have two copies of THBS1) to mimic protective decreased expression alleles described in humans. Double ltbp4;dmd and thbs1b;dmd mutants show partial rescue of dmd mutant muscle integrity and increased survivorship compared to dmd single mutant siblings. A long-term goal of our work is to further define the cell-specific regulation mechanisms that control TGFβ signaling through LTBP4 and THBS1 to potentially identify novel therapeutic targets.
Keywords: Zebrafish, Dystrophy, Tgf-beta