Brian R. Rood, MD is an Assistant Professor of Pediatrics at the Children's National Medical Center. Dr. Rood has shown the importance of chromosome 17p deletion and epigenetic inactivation in the silencing of the tumor suppressor gene HIC-1 in medulloblastoma. With the support of an Avery Research Scholars Award from the Children's Research Institute, Dr. Rood used gene expression profiling to identify potential targets of HIC-1 mediated transcriptional repression. He has also begun using siRNA to silence HIC-1 in order to confirm one of these targets, PDGF-C. With the support of a Mentored Clinical Scientist Development Award, Dr. Rood plans to use this strategy to demonstrate the role of HIC-1 inactivation in the establishment of a growth stimulatory autocrine loop involving PDGF-CC. The Specific Aims of this project are: 1) To evaluate medulloblastoma cell lines for the presence of PDGF-CC autocrine activity, 2) To investigate the mechanism of HIC1 mediated PDGF-C repression and 3) To determine whether HIC1 inactivation establishes an autocrine signaling loop and identify the receptors activated by PDGF-CC. Dr. Rood will obtain the technical skills and guidance necessary to carry out this investigation with co-mentorship from three sources: Dr. Stephan Ladisch, an expert in tumor biology, Dr. Vottorio Gallo, a leading expert in neural stem cell signaling and biology, and Dr. Jeffrey Toretsky, an expert in tumor signal transduction. With the additional resources and formal training provided by the Career Development Program established at CNMC, the short-range scientific goals of this project can be accomplished. With additional guidance by Dr. Roger Packer, a renowned clinical neuro-oncologist, Dr. Rood will develop an independent career in translational research within 5 years. The long-range goal of this work is to broaden the understanding of brain tumorigenesis to foster the development of novel targeted therapies. Brain Tumors are the number one cause of cancer related death in children. Current therapies, effective in a minority of malignant tumors, are very toxic and leave children with significant long term sequelae. An era of targeted, relatively non-toxic, molecular therapies is just beginning and greater understanding of the molecular biology of brain tumors is required to develop these agents. This project seeks to investigate the biologic role of one of these potential therapeutic targets, the PDGF signaling pathway.