Heart Development and Regeneration
- The lab has is known for discovering fundamental processes of heart development. These include the first demonstration that the embryonic heart forms in response to naturally occurring Wnt and TGFb inhibitory proteins. Dickkopf-1 and Cerberus are particular important inhibitors in heart formation and function by locally blocking signaling from Wnt and the TGFb family member Nodal, respectively, in the region of the mesoderm destined to become heart. Wnt inhibition induces cardiovascular progenitors while TGFb inhibition is responsible for reprogramming the SWI/SNF chromatin remodeling complex to activate cardiomyogenic genes. Once induced, Notch and other signaling pathways then cause the subsequent segregation of lineages within the early heart.
- The adult human heart retains little regenerative capacity, and hence cannot replace the muscle cells that are lost or damaged by injury, such as myocardial infarction. We have probed mechanisms of possible therapeutic potential for enhancing the heart’s native regenerative capability. These include stimulating differentiation of progenitors through small molecule mediators and by stimulating replication of endogenous heart muscle cells.
Conrad Prebys Center for Chemical Genomics at the Sanford-Burnham Medical Research Institute
Calcium transients of hiPSC-derived cardiomyocytes imaged in high throughput by the Kinetic Imaging Cytometer, see paper by Cerignoli et al., J. Pharm. Tox. Methods (2012)
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Screening a phenotypic assay of stem cell differentiation against a collection of drug-like small molecules led to the discovery of ITD-1, which stimulates progenitor cells to initiate cardiomyocyte differentiation. ITD-1 (inducer of TGF-beta degradation) is the first selective small molecule inhibitor of TGF-beta. See papers by Willems et al., Cell Stem Cell (2012) and Schade et al., J. Med. Chem. (2012).