CLICK ON weeks 0 - 40 and follow along every 2 weeks of fetal development
Developmental biology - Gene Therapy|
Improving DMD Heart Function In Mice
"We'd been using skeletal muscle as a platform to understand NF-
Using a mouse model of DMD (mdx), the team established NF-
Their next experiments revealed cardiomyocyte NF-
"This mechanism was unexpected," says Guttridge. "We thought that when the pathway was ablated [removed], the global gene expression pattern would be down-regulated [suppressed] because NF-
The team's next series of experiments uncovered that even though NF-
"When we dug deeper to find out how and exactly what genes it was repressing, we saw mostly calcium-handling genes like Slc8a1. Without proper mobilization of calcium, the heart doesn't contract normally," adds Guttridge, "The reason NF-
While it is understood that the pathology of dystrophic hearts is caused by disruption of calcium equilibrium, the exact mechanisms driving this disruption had not previously been explored. Furthermore, these findings have important implications for the treatment of heart failure in multiple conditions including diabetes and following ischemia-reperfusion or 'heart attack' injuries. Perhaps more importantly, these findings highlight that targeting NF-
"I'm very excited about these findings! As a scientist, you follow your hunches and try to vigorously test your hypotheses. It's so satisfying to have found a pathway that we believe contributes to the pathology of DMD, not just in skeletal muscle but also in the heart. This gives us hope that a drug can be developed that has the possibility of improving patients' lives."
Duchenne muscular dystrophy (DMD) is a neuromuscular disorder causing progressive muscle degeneration. Although cardiomyopathy is a leading mortality cause in DMD patients, the mechanisms underlying heart failure are not well understood. Previously, we showed that NF-
Authors: Jennifer M. Peterson, David J. Wang, Vikram Shettigar, Steve R. Roof, Benjamin D. Canan, Nadine Bakkar, Jonathan Shintaku, Jin-Mo Gu, Sean C. Little, Nivedita M. Ratnam, Priya Londhe, Leina Lu, Christopher E. Gaw, Jennifer M. Petrosino, Sandya Liyanarachchi, Huating Wang, Paul M. L. Janssen, Jonathan P. Davis, Mark T. Ziolo, Sudarshana M. Sharma and Denis C. Guttridge.
The authors declare no competing financial interests.
Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.
About the study
Dr. Olson is Professor and Chair of Molecular Biology at UT Southwestern. He holds the Pogue Distinguished Chair in Research on Cardiac Birth Defects, the Robert A. Welch Distinguished Chair in Science, and the Annie and Willie Nelson Professorship in Stem Cell Research. He is also the scientific founder of Exonics Therapeutics, launched in February 2017 to advance and commercialize his research.
The study was supported, in part, by Exonics Therapeutics Inc. and grants from the National Institutes of Health, the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, and the Robert A. Welch Foundation.
Dr. Olson's team collaborated with the Royal Veterinary College. The RVC's dog colony program was supported by grants from the Wellcome Trust, Muscular Dystrophy UK, and Duchenne Ireland.
Disclosure statements: Dr. Eric Olson is a scientific co-founder of, and consultant for, Exonics Therapeutics, and has license and investment interests with the company. Dr. Leonela Amoasii is a consultant for Exonics Therapeutics and is listed as co-inventor, along with Dr. Olson, of the strategy presented in the study.
About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution's faculty has received six Nobel Prizes, and includes 22 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 15 Howard Hughes Medical Institute Investigators. The faculty of more than 2,700 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 2.4 million outpatient visits a year.
Return to top of page
An image of a histological section taken from an mdx heart courtesy of Dr. Denis Guttridge of the Medical University of South Carolina. Image Credit:Dr. Denis Guttridge of the Medical University of South Carolina. Modified from a supplemental figure in a Nature Communications article by Peterson et al (Nature Communications, volume 9, Article number: 3431 (2018), in accordance with the article's Creative Commons license.