Research


Cardiogenesis
The four-chambered mammalian heart develops from two fields of cardiac progenitor cells (CPCs) distinguished by their spatiotemporal patterns of differentiation and contributions to the mature heart. The first heart field differentiates earlier in lateral plate mesoderm, generates the linear heart tube and ultimately gives rise to the left ventricle. The second heart field (SHF) differentiates later in pharyngeal mesoderm, elongates the heart tube, and gives rise to the outflow tract (OFT) and much of the right ventricle. Because hearts in lower vertebrates contain a rudimentary OFT but not a right ventricle, the existence and function of SHF-like cells in these species remained a topic of speculation. We recently demonstrated that the zebrafish, a lower vertebrate with a single ventricular chamber, harbors a SHF population that (1) contributes 3 cardiovascular lineages to the linear heart tube, (2) gives rise to the distal ~half of the single ventricle and OFT, and (3) expresses the integral TGFb pathway component ltbp3. Most of our current studies are aimed at understanding the genetic and cellular processes controlling FHF and SHF development. Using transcriptional profiling from FACS-sorted progenitors from various fluorescent transgenic strains, we identified several new genes and are dissecting their critical roles in FHF and SHF specification and fate decisions. With a bounty of new transgenic reagents in hand, we have also begun more sophisticated genetic and chemical screens to identify new pathways required for both FHF- and SHF-mediated cardiac development.

Pharyngeal Arch Artery Development
Malformations involving the large arteries that exit the heart (e.g. “the great vessels”) are common congenital disorders. In most circumstances, the genetic basis for these abnormalities has not been identified. During embryogenesis, the great vessels arise from six pairs of bilaterally symmetrical arteries embedded within the pharyngeal arches that undergo extensive remodeling to produce the asymmetric pattern present at birth. Although the remodeling aspects have been extensively studied, the developmental origin of pharyngeal arch arteries (PAAs) and the genetic programs regulating their establishment remain elusive. We have recently initiated studies to understand the cellular source of PAA endothelium and discover the genetic pathways mediating their specification. 

Heart Regeneration
Ischemic heart disease is among the leading causes of morbidity and mortality in the United States and worldwide. Current therapies are designed to minimize cardiomyocyte (CM) loss and scar formation, yet these regimens are suboptimal as they only delay disease progression. Conversely, cardiovascular regenerative medicine holds the promise of fully restoring heart function following injury through generation of new, healthy tissue. Unlike mammals that show limited regenerative capacity, zebrafish naturally achieve heart repair within 1-2 months following ventricular apex amputation or cryoinjury. We are currently dissecting the role of several developmental pathways in cardiomyocyte regeneration. Moreover, we are interested in learning what tissues and signaling programs promote cardiomyocyte cell division through new screening strategies.