Stanford scientists will direct a multidisciplinary, multi-institutional team focused on understanding in detail how tiny mutations in a protein, myosin, can cause the classic features of cardiomyopathy.
June 24, 2019 - By Bruce Goldman
The National Institute of General Medical Sciences has awarded a five-year, $10 million grant to a multidisciplinary, multi-institutional team of scientists led by School of Medicine researchers that will try to gain insights into a common cause of heart failure.
The lead Stanford researchers are James Spudich, PhD, professor of biochemistry; Daniel Bernstein, MD, professor of pediatrics; and Sean Wu, MD, PhD, associate professor of cardiovascular medicine. Co-investigators are Alexander Dunn, PhD, associate professor of chemical engineering, and Kathleen Ruppel, MD, senior scientist in biochemistry.
The Stanford-led team — which also includes researchers from the University of California-Santa Barbara, the University of Washington and the Institut Curie in Paris — will seek a deep understanding of exactly how minute changes within genes, and the resulting alterations in the proteins for which those genes are recipes, can give rise to complex disease profiles.
The grant came about as the result of a national competition, with each institution limited to a single submitted application. This granting mechanism was initiated in 2017 with the express intent, according to the NIGMS, of supporting projects that “address complex and challenging biomedical problems.” Spudich and Bernstein’s proposed project was selected through an internal review process that took place at Stanford. It was one of only three such proposals the NIGMS selected this fiscal year for grants totaling an estimated $27 million over a five-year period.
The team will focus on a particular protein, myosin, which is responsible for cell contraction in numerous tissues and organs, notably including skeletal muscle and the heart. Mutations in myosin have been implicated in a variety of cardiomyopathies, irregularities in heart-muscle function that affect 1 in every 500 people and are major causes of heart failure and sudden death. Myosin mutations can also cause skeletal muscle diseases that lead to impaired motor function.
Spudich is the Douglass M. and Nola Leishman Professor of Cardiovascular Disease. Bernstein is the Alfred Woodley Salter and Mabel G. Salter Endowed Professor in Pediatrics and the school’s associate dean for curriculum and scholarship. The two scientists and their colleagues intend to develop a comprehensive understanding of how the hallmarks of various forms of cardiomyopathy can arise from minute, mutation-induced variations in individual myosin molecules. They will conduct their examination at several different scales, observing methodically how disease-causing alterations in myosin affect the structure and mechanical properties of the mutated protein and of the contractile subcellular entities of which it is a crucial component (subcellular entities of interest in the heart include repeating myosin-rich filamentous subunits called myofibrils).
The investigators will also introduce specific mutations to human induced pluripotent stem cells in order to monitor the resulting dysfunctions at the cell and tissue level, and they will develop computational models to extend their findings across a broad spectrum of contractile-protein mutations.
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