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Our goal is to gain a detailed understanding of the mechanisms leading to the pathological consequences of heart disease, and to regenerating new heart muscle. Heart disease remains a major cause of mortality and morbidity in developed countries. Unfortunately, repair of heart muscle following injury is clinically negligible; instead, scar tissue replaces damaged myocardium leading to impaired heart function and a reduction in quality of life. Nonetheless, a modest level of regeneration occurs; consequently, our strategies include development of drugs to enhance new muscle from stem cells in the patient’s heart and as well as other drugs to protect the heart from chronic injury.
To translate this knowledge into clinical therapies, we have devised high throughput screens (HTS) to discover cellular proteins that can be targeted by drugs to achieve therapeutic heart regeneration, or protection from cell death and pathological scar spreading after injury. The chemical biology and functional genomics approaches are presently leading to a comprehensive, systems-level view of key cellular processes and signaling proteins underlying regenerative and protective mechanisms. These screens involve traditional HTS approaches, and also image-based analysis of phenotypic assays, known as high content screens (HCS), screened against libraries of pathway modulators, microRNAs, and siRNAs to identify novel pathways and potentially druggable targets. This approach, in collaboration with the Conrad Prebys Center for Chemical Genomics, has led to a number of cardiogenic small molecules that function by activating or inhibiting cellular proteins involved in cardiogenesis.