Jeffrey Robbins, Ph.D. Cincinnati Children’s Hospital
Dr. Robbins received his Ph.D. in Genetics and Development in 1976 from the University of Connecticut and, after taking a short fellowship with Jerry B. Lingrel, was appointed as Assistant Professor in the College of Medicine at the University of Missouri-Columbia. He rose through the academic ranks, obtaining tenure, and left Missouri to join the Department of Pharmacology and Cell Biophysics at the University of Cincinnati College of Medicine in 1987. In 1993, he moved to the Cincinnati Children’s Hospital to start the new division of Molecular Cardiovascular Biology and in July 2009, formed the Heart Institute, integrating the basic and clinical arms of Pediatric Cardiology. He currently is Professor of Pediatrics, Chair, Division of Molecular Cardiovascular Biology, Associate Chair of the Research Foundation, and Executive Co-Director of the Heart Institute. He has won a number of teaching and research awards, including the Golden Apple awarded by the medical students for excellence in teaching, the Kaplan Award for innovative research, the National Research Achievement Award from the American Heart Association, the Presidential Award from the International Society for Heart Research, the Rieveschel Award for Outstanding Research Achievements, the Drake Medal and the Distinguished Scientist Award from the American Heart Association and the Lucian Award for Innovation in Cardiovascular Research. He was an Established Investigator of the American Heart Association as well and recently named the Fyler Visiting Professor at Harvard. In 2014, he was awarded the Lucian Prize for Innovations in Cardiovascular Research.
Alzheimer’s of the Heart: Proteotoxicity and its Role in Cardiovascular Disease
Some years ago, our group discovered that, during cardiovascular disease occurring as a result of diverse primary etiologies, proteotoxicity became a convergent, pathogenic pathway. Although not the primary etiology, once triggered, proteotoxic processes contribute to decreased cardiac function and the development of heart failure. By modeling the human desminopathies in mice, we were able to pinpoint a key event in the pathogenesis; the formation of toxic, pre-amyloid oligomers, similar to the toxic, soluble species that are found in many of the neurodegenerative diseases. After discovering the existence of these in the mouse model, we went on to show that they were absent in healthy human hearts but present in significant concentrations in human hearts derived from patients suffering from heart disease (Figure 1).
Figure 1. Immunohistochemistry-treated sections form a normal human heart (left) and a heart taken from a 36-year old person who died of idiopathic dilated cardiomyopathy (right). The sections were stained with cardiac troponin I (red) to identify the cardiomyocytes and with A-11 (green), an antibody obtained from Charles Glabe that detects toxic pre-amyloid oligomers.
We have shown that clearance of the toxic oligomer results in restoration of cardiac function and decreased cardiac pathology and therefore, tested if the lysine-specific molecular tweezers, CLR01, could effectively decrease the formation of nascent oligomer and help the cardiomyocyte’s native clearance mechanisms to decrease the toxic load of pre-existing pre-amyloid oligomers. Our recent study showed that CLR01 not only did both, but also reduced accumulation of toxic αB-crystalline aggregates in mouse heart (Xu et al., J. Am Heart Assoc., 2017), suggesting that CLR01 could be developed as a therapeutic agent for cardiomyopathies caused by proteotoxicity.