My research is focused on understanding specific aspects of organogenesis that are pertinent for understanding human structural birth defects. Our major focus is on the basic development of the diaphragm and the early lung, as birth defects called “congenital diaphragmatic hernias” or “CDH” cause devastating problems in humans and are associated with abnormal development of the diaphragm and of the lungs.
We mainly utilize mouse genetic approaches to understand mechanisms of development. As genes that are necessary for diaphragm and lung development often have other important functions, knock out mice have been rarely useful as models. Therefore, we use conditional gene deletion using cre/lox technology, in vitro gene modification, and other technologies to investigate the effects of altered gene dosage on development. The transcription factor genes, Gata4 and its cofactor Fog2 are both important for diaphragm and lung development. They are both needed for normal lobar patterning in the lung, and altered gene dosage of both lead to a variety of diaphragmatic defects. We utilize Gata4 and Fog2 mutant and/or targeted mouse lines to investigate specific mechanisms of development as well as mouse lines targeted for other genes that are important for lung and diaphragm development.
Forward genetic screening is a valuable tool for identifying hypomorphic mutations causing a variety of phenotypes in mice or for identifying naturally occurring mutations in other inbred populations. We are currently pursuing two forward genetic screening projects. First, in mice, ENU mutagenesis is used to induce random point mutations and screening is done to recover mutant lines that have diaphragm defects or major lung lobar defects. Second, in swine, relatively inbred populations are screened for the presence of specific structural birth defects including CDH, obstructive uropathy (megabladder phenotype), congenital heart disease, myelomeningocele, and orofacial clefting. The screen in swine is done in collaboration with North Carolina State University and we hope it will lead to the identification of new gene functions as well as the development of new large animal models for research.
Since we have a focus on human disease, we also evaluate candidate disease genes for sequence changes in affected patients. We enjoy building collaborations with clinicians and other research labs world wide.