March 11, 2005

Awards help trio carry on research into birth defects

Awards help trio carry on research into birth defects

Three Vanderbilt University Medical Center researchers were recently awarded Basil O'Connor Starter Scholar Research Awards from the March of Dimes. These prestigious awards support research on birth defects by young scientists just embarking on independent research careers.

Michael K. Cooper, M.D., assistant professor of Neurology and Vanderbilt Kennedy Center Investigator, studies the role of Hedgehog proteins — one of several secreted signaling proteins required for normal embryonic development — in the developing nervous system. Disruptions in the Hedgehog pathway lead to a wide range of birth defects, including holoprosencephaly, which involves the face and brain.

Hedgehog proteins are unique because cholesterol participates as a cofactor and covalent adduct during their biogenesis. Cooper's previous research has helped reveal an additional requirement for adequate cholesterol levels in cells that receive Hedgehog signals during development. However, the precise role of the cholesterol adduct on Hedgehog protein function remains unknown. The March of Dimes award will support Cooper in his studies of these proteins and their modification by cholesterol in developing zebrafish to study further the role of cholesterol in Hedgehog signaling.

Laura Anne Lee, M.D., Ph.D., assistant professor of Cell and Developmental Biology, is examining cell cycle regulation in the fruit fly Drosophila. Lee and colleagues recently identified Drosophila lines with mutations in the homolog of the human disease gene microcephalin.

Mutations in the human microcephalin gene result in primary microcephaly (“small head” in Greek), a developmental condition in which cerebral cortex size is severely reduced. Little is known about the cellular function of microcephalin, and no animal models of this disease have been reported to date. Drosophila microcephalin mutants undergo defective cell divisions, suggesting an explanation for the small brain size in individuals with primary microcephaly. This award will support studies to further elucidate the normal developmental and cell cycle role of microcephalin.

Christopher B. Brown, Ph.D., assistant professor of Pediatrics and Pharmacology, is investigating the molecular mechanisms involved in early heart development and remodeling. Defects in cardiovascular development are among the most common birth defects, occurring at rates of around one in 100 births.

Brown has demonstrated that a class of signaling proteins, called semaphorins, plays a critical role in early cardiac development. Mice that lack a particular semaphorin develop a birth defect in which the aorta and pulmonary artery fail to separate and the aorta does not connect to the systemic circulation. With support from this award, Brown will probe further the role of semaphorins in the differentiation, proliferation and survival of cardiac neural crest cells, which regulate the formation of the aorta and pulmonary artery and connect these vessels to the correct ventricles in the mature, multi-chambered organ.

Founded in 1938, the March of Dimes is a national nonprofit health agency dedicated to improving the health of babies by preventing birth defects and infant mortality. This mission is carried out through the support of research, community service, education and advocacy programs.