Overview from the Director
The Pediatric Surgical Research Laboratories were established in 1973 under the directorship of Patricia K. Donahoe, M.D., Chief Emeritus of the Pediatric Surgical Services.
The Pediatric Surgical Research Laboratories focus on developmental biology and how the tools of development and molecular biology can be brought to bear on children with congenital abnormalities. The laboratory has also focused on signals controlling fetal development, particularly fetal inhibitors, attempting to development them as nontoxic therapeutic drugs which can be targeted to tumors which express receptors for the fetal grown inhibitors.
The laboratory was the first to clone the gene for Mullerian Inhibiting Substance which is a natural feta testicular inhibitor that causes regression of the Mullerian duct, the anlagen of the uterus, Fallopian tube, and vagina, making that organ system totally disappear in the normal male embryo. The laboratory has discovered that ovarian, endometrial, and cervical tumors, which are of Mullerian duct origin, express the receptors and are growth inhibited by MIS in a manner which is characterized by cell cycle arrest and apoptosis.
The laboratory has recently discovered receptor expression in breast and prostate tissues and in cancers emanating from these organs. MIS also inhibits growth of these tumors and the mechanism of action of this growth arrest has been elucidated.
The laboratory along with a number of others has cloned the MIS type II receptor and a number of type I receptors that are tissue , activin, and BMP’s. MIS type II receptor has been?specific for MIS and for TGF found in Leydig cells showing that MIS blocks testosterone synthesis at the transcription level by inhibiting the promoter region of the 17 lyase enzyme. The laboratory has also developed a sensitive MIS Elisa assay which has been useful in the clinical management of babies with ambiguous genitalia and adults with MIS producing granulosa cell tumors. Together with Biotechnology partners, MIS is being scaled up for use in preclinical and clinical trials against ovarian cancer and other human tumors that are responsive to MIS.
The laboratory also focuses on patients with congenital anomalies in the hopes of identifying the genetic defects that lead to these anomalies by studying families with these defects. The laboratory has received funding for a Program Project from the National Institutes of Child Health and Development to study lung hypoplasia in patients with congenital diaphragmatic hernia (CDH). Using a candidate gene approach, evolutionarily conserved genes discovered to be important in lung development in drosphillia, avian, rodent, and humans will be studied. Genes discovered to be abnormal in patients with CDH will be used as targets to develop therapeutics that can be potentially delivered in utero to avert or ameliorate the congenital anomalies.
Once the infrastructure for the study of patients with CDH is in place, it will be used to study patients with common congenital anomalies of the genitourinary tract such as vesicoureteral reflux and ueteropelvic junction obstruction, as well as children with recurrent urinary tract infections due to bullous cystitis cystica.
Given the emphasis of the laboratory also on the study of gut patterning and the formation of the enteric nervous system, we will also use this infrastructure to study patients with Hirschsprungs’ Disease and Neuronal Intestinal Dysphasias.
