February 2010

Heart Matters

Eric N. Olson

Professor and chairman of the department of molecular biology, University of Texas Southwestern Medical Center

Science-Focus---Olson
Eric N. Olson and Willie Nelson. The iconic singer/songwriter and his wife, Annie, established a professorship to support Olson’s work on cardiac stem cells.

It’s appropriate that one of Eric N. Olson’s favorite tunes to play with his rock band, the Transactivators (in which Olson plays guitar and harmonica), is Neil Young’s “Heart of Gold.” While each organ in the human body is a complex, fascinating and, in most cases, essential physiological machine, in Olson’s view, any discussions as to which organ should be considered the most vital begins and ends with the heart.

“The heart is incredibly unique,” he says. “It performs nonstop rhythmic contractions every second, and it’s a wonderful model for understanding how genes are coordinately regulated and control organ formation. Plus, adult cardiac cells never divide, making them an ideal system to study the cell cycle.”

“Oh, and of course, unlike some other organs, the heart lacks an intrinsic mechanism to repair itself,” he adds. “So, cardiovascular disease still remains the No. 1 killer in the United States, while congenital heart defects are the most common birth defects seen in humans: They occur in about 1 percent of all live births.”

It’s the latter statistic that has been a driving force for Olson’s research at UT-Southwestern; since arriving in 1995 from the M.D. Anderson Cancer Center, his group has been hard at work identifying the genes and transcription factors responsible for forming the heart in developing embryos and analyzing how defects in those genetic networks lead to congenital heart disease.

The work has been a natural progression from Olson’s earlier— and continuing— studies into skeletal and smooth muscle differentiation, through which he discovered several transcription factors involved in that process and realized many of them had similar roles in cardiac muscle.

Olson combines genetic and biochemical approaches to discover novel cardiac transcription factors, including mutational studies in Drosophila, which has turned out to be an excellent model organism for studying heart defects. “It may not seem readily apparent, but many key muscle transcription factors were first discovered in fruit flies,” he says, noting that the fruit fly heart, a simplistic linear pump, closely resembles the heart tube in early mammalian embryos.

Olson notes that his field has been quite dynamic recently (due in no small part to his efforts, which include the discovery of the transcription cofactor myocardin and the identification of both calcineurin and histone deacetylases as regulators of cardiac hypertrophy). “We’ve made some dramatic progress this past decade,” he says. “We’ve gone from knowing virtually nothing about the molecular blueprint for heart development to knowing most of the regulators involved, though we still need to tease out how they all fit together.”

A new wrinkle in that blueprint, and one that’s been a significant focus of Olson’s work the past few years, is the emerging role of microRNAs in heart development and disease. From identifying the importance of miR-126 in vascular integrity to miR-133’s role in cardiomyocyte proliferation, “we’ve managed to uncover a treasure trove of new regulators that affect virtually every process associated with heart disease,” he says, “such as fibrosis, hypertrophy and atrophy and blood vessel formation.”

Combining the potential power of RNA silencing with existing technologies for delivering therapeutics to the heart, Olson is preparing to take these microRNA discoveries to the treatment stage; he even started up a biotech company, called miRagen Therapeutics, to help him with this process.

Journal of Biological Chemistry research highlight: Down Syndrome Critical Region-1 Is a Transcriptional Target of Nuclear Factor of Activated T Cells-c1 within the Endocardium during Heart Development. JBC 282, 30763-30679.

More Heart Matters with Daria Mochly-Rosen 

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