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Pediatric

Director:
Patricia K. Donahoe, M.D.

Associate Director:
David T. MacLaughlin, Ph.D.

Principal Investigators:
Drucilla Roberts, M.D.
Jay Schnitzer, M.D., Ph.D.
Lizabeth Perkins, Ph.D.
Jose Teixeira, Ph.D.
Shyamala Maheswaran, Ph.D.
Allan M. Goldstein, M.D.
Daniel Doody, M.D.
Daniel Ryan, M.D.

Postdoctoral Fellows:
David Kling, Ph.D.
Nelson Alexander Arango, Ph.D.
James Lorenzen, Ph.D.
Maria Loscertales, Ph.D.
Vandana Gupta, Ph.D.
Srini Krishnamoorthy, Ph.D.
Martha Reed
Yong Zhan, M.D.

Surgical Fellows:
Pradeep Nazarey, M.D..
Elizabeth Renaud, M.D.
Akemi Kawaguchi, M.D.
Hirofumi Kawakubo, M.D.

OB/GYN Fellows:
Thanh Barbie, MD..

Predoctoral students:
Nina Martrenel
Katherine Harvey

Study Coordinator:
Meaghan Russell, M.P.H.

Collaborators:
Bernard Kinnane, M.D.
Lewis Holmes, M.D.
Barbara Pober, M.D.
Thilo Stehle, M.D.
Jeff Gelfand
Arlan Fuller, M.D.
Jay Wilson, M.D.

Current Research Projects:

The Pediatric Surgical Research Laboratories focus on areas of Developmental Biology, which hold promise for clinical application to benefit the pediatric population or may benefit selected adult patients. Patricia Donahoe, M.D., David MacLaughlin, Ph.D., and Jose Teixeira, Ph.D., have purified and cloned TGFb family of cytokines, including Mullerian Inhibiting Substance (MIS) and its receptors which direct normal male phenotypic development in the fetus by causing regression of the female reproductive duct. This fetal regressor, MIS, has potential as a novel treatment for cancers arising in the female reproductive tracts of adults. Work is underway at the MGH to scale-up production in mammalian cells and in tobacco in collaboration with biotech companies, for use of MIS in preclinical tests against human ovarian cancer. The preclinical anticancer studies are being done in vitro and in vivo by Drs. Donahoe and MacLaughlin with Elizabeth Renaud, M.D., a surgical fellow from Boston University. Thilo Stehle, Ph.D., from the Pediatric Developmental Immunology Laboratory, is using the C terminal fragment of MIS which has been purified by Dr. MacLaughlin to homogeneity by FPLC, for crystallography and for cocrystallography with the MIS receptors. Recent studies of Drs. Donahoe and MacLaughlin reveal that human ovarian cancer established cell lines and primary ascites epithelial cells bind labeled MIS by flow cytometry, express MIS type II receptor mRNA by RTPCR and northern analysis, and are growth inhibited by MIS in colony inhibition assays.

Drs. Teixeira, MacLaughlin, and Donahoe have the MIS type II and type I receptors and the receptor specific Smads important in initiating downstream signaling. Based upon observations of low testosterone in animals which overexpress MIS, Dr. Teixeira has also elucidated how steroid production is regulated in developing and adult Leydig cells by downregulation of transcription of P450c17, a rate limiting enzyme in the production of testosterone. He is now pursuing the molecular mechanism by which this occurs.

Dr. Maheswaran, and Dorry Segev, M.D., a surgical resident from Johns Hopkins, have analyzed downstream proteins that transduce the MIS signal, and have identified genes regulated by MIS. They have found that MIS via its receptors induces the CDK inhibitor, p16, and the NFkB pathway to cause growth arrest. Dr. Maheswaran has also documented expression of MIS type II receptor in prostate and breast cancers and response to MIS in vitro and in vivo.

Dr. MacLaughlin has developed a radioimmuno assay to detect granulosa and sex cord tumors in children and adults, and to assist in the differential diagnosis of infants with intersex abnormalities, where it serves as a testicular or Sertoli cell marker. Clinical trials are planned which have resulted directly from basic laboratory research. The use of recombinant human MIS in a phase I clinical trial in patients with human ovarian cancers, led by Drs. Donahoe and MacLaughlin, is the one most close to clinical application.

Jay Schnitzer, M.D., Ph.D., David Kling, Ph.D, and Pradeep Nazarey, M.D., a surgical fellow from the University of Massachusetts, are examining factors in the MAP kinase pathway affecting branching morphogenesis of the lung, in hopes of defining factors contributing to, and possibly providing a therapeutic target corrective for, the lethal hypoplasia accompanying Congenital Diaphragmatic Hernia (CDH). They are also studying the role of anti-oxidants in the etiology of CDH. Dr. Schnitzer will use rodent models of CDH to screen for candidate genes which can rescue the phenotype of CDH prior to conducting a mutational analysis of patients with CDH.

Daniel P. Doody, M.D., Daniel P. Ryan, M.D., and Dr. Schnitzer have established new paradigms in clinical management in Acute Respiratory Distress Syndrome (ARDS) in patients with burns, viral infections, and trauma, using permissive hypercapnia, which have resulted in improved survival in infants and children. They adapted Extracorporeal Membrane Oxygenation (ECMO) protocols for use in older children and adults. These protocols have resulted in survival of patients unable to be weaned from the pump after open heart surgery and in previously terminal patients with adult ARDS.

Lizabeth Perkins, Ph.D. has cloned the gene corkscrew and has characterized the role of this tyrosine phosphatase using Drosophila genetics as part of a broader effort to define the tyrosine kinase pathway downstream of growth hormone receptors. James Lorenzen, Ph.D. and Dr. Perkins have identified and are characterizing novel cytosolic partners functioning downstream of corkscrew including molecules involved in nuclear import. Dr. Perkins is now using a non-lethal hypomorphic mutant of Csw to screen for genes involved in tracheal development. She has identified six regions of the Drosophila genome which enhance lethality and is using them to identify genes and pathways important in tracheal development. Candidates from this screen will be used in a mutational analysis of patients with Congenital Diaphragmatic Hernia.

Dr. Drucilla Roberts is using retroviral misexpression techniques in the chick embryo to explore branching morphogenesis in the lung. Drs. Roberts, Perkins, Schnitzer, and Donahoe, and our collaborators Bernard Kinane, M.D., Marcy MacDonald, PhD, Lewis Holmes, M.D., Barbara Pober, M.D., and Jay Wilson, M.D., are using comparative genetics to examine candidate genes that may be mutated in Congenital Diaphragmatic Hernia. They will use different animal models, from Drosophila to humans to study these genetic interactions, then determine if candidate genes derived from these respective screens are abnormal in patients with CDH. The animal models can be used as a small molecule screen for pharmacologicals to treat CDH in utero. So far, over 70 patients have been enrolled in the study and cell lines established for patients, parents, and siblings.

Dr. Allan Goldstein, M.D., and Dr. Roberts, are also using retroviral misexpression in chick embryos to study normal midgut and hindgut patterning and applying their findings to the clinical syndrome of Hirschsprung’s disease.

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