Congenital defects occur in up to 10% of all human pregnancies. A large percentage of these defects involve the cardiovascular system. In a broad sense, my lab is interested in defining the molecular signals guiding the early patterning of the vertebrate embryo with emphasis on organogenesis and cardiovascular development. Through an understanding of normal development we hope to better understand how congenital defects may occur.
The early patterning of the vertebrate embryo results from a complex milieu of signals to guide growth, differentiation and migration of cells to their proper position and specification. Utilizing modern genetic techniques, we are attempting to dissect these signals through lass and gain of function experiments. As an example, utilizing the Cre/LoxP and Flp/Frt recombination systems, we have targeted the murine Fgf8 gene locus to perform loss of function studies. Using this approach, we have determined that Fgf8 is required not only during gastrulation, limb outgrowth, and CNS development, but is also required as a left-right axis determinant as well. From its earliest stages, the cardiovascular system is patterned in a left-right asymmetric manner. Loss of Fgf8 function can result in a phenotype similar to the human "asplenia" syndrome where left-sided structures are mis-specified as right. This results in characteristic complex cardiovascular defects.
We are now primarily interested in identifying other genes that establish and pattern the cardiovascular system, with particular attention paid to those signals involved in left-right determination. Screening strategies to identify new candidate genes will be performed. Studies to determine downstream targets as well as modifiers of Fgf8 signaling will also be pursued. In addition we are generating Cre-expressing transgenic mouse lines to perform tissue-specific elimination of Fgf8 to better define its role in various organ system development. Similar strategies will also be used to examine and target other candidate genes to study early patterning of the vertebrate embryo.
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