[대학원 생명과학과 세미나 안내]
연사 : 고창원 교수(부산대학교, 응용의학부)
연제 : Role of Post-Translational SUMOylation in Heart Failure: Small Change, Big Impact
일시 : 2020년 12월 18일 (금) 오후 5시
장소 : 온라인 화상 강의로 진행됩니다.
초청교수 : 지성욱 교수
Abstract
Duchenne Muscular Dystrophy (DMD) is a genetic, muscle degenerative disorder whose major cause of death is heart failure (HF). We developed a novel therapy for HF based on the overexpression of small ubiquitin-like modifier type 1 (SUMO1) protein that improves cardiac function by activating sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) pump. This concept has been demonstrated by therapeutic efficacy in animal models of HF. Recently, we found that levels of SUMO1 and SUMOylated SERCA2a were reduced in hearts of DMD mice, similar to that seen in failing hearts. Our objective is to investigate whether SUMO1 activation has benefits for cardiac function in DMD mice.
SUMO1 gene therapy was performed in 12-month-old dystrophin-utrophin double knockout heterozygous (dKO+/-) mice via tail-vein injection with 5 × 1010 viral genomes per mouse of AAV.SUMO1. 16-month-old dKO+/- mice were treated with either N106 (10 mg/kg/day) or vehicle (10% DMSO, 10% Tween-80, 80% Saline) by gavage feeding for one or two months. Two months after gene transfer, fractional shortening increased significantly and molecular markers of hypertrophy and fibrosis were reduced in AAV.SUMO1 injected dKO+/- mice. Additionally, administration of N106 significantly improved contractile function and reduced left ventricle chamber enlargement. Additional benefits such as decreased cardiac and skeletal muscle fibrosis were observed in dKO+/- mice treated with N106.
These data suggest that activation of SERCA2a SUMOylation might be a novel and promising strategy for treating DMD.