EXCEED THE SPACE PROVIDED. Medulloblastoma is the most common malignant brain tumor of childhood. We have reported that the expression of the neurotrophin-3 (NT-3) receptor, TrkC, by medulloblastomas correlates with their clinical outcome and that NT-3/TrkC activation induces apoptosis in medulloblastoma cells. Mouse models that aremanipulated more easily than human tumors and less artifactual than cell lines will facilitate future studies of tumor apoptosis. PATCHED is the tumor suppressor mutated in Gorlin's Syndrome patients who display increased incidence of medulloblastoma. Heterozygous patched (ptc+/-) mice develop spontaneous medulloblastomas that closely resemble their human counterparts including their heterogeneity. Our extensive hybridization microarray analysis of primary human medulloblastomas indicates that characteristics such as tumor histology and patient survival correlate with specific gene expression patterns. Similar chip analysis of ptc+/- mouse tumors will determine if their expression profiles correlate with biological properties and confirm their suitability as models for humantumors. As a most promising medulloblastoma model, the ptc+/- mouse enables us to address the following questions. How diverse are ptc+/- mouse tumors and how similar are they to human tumors? Does NT-3 induce apoptosis in ptc+/- mouse tumors in vitro! Does NT-3/TrkC-induced apoptosis limit the growth of ptc+/- mouse tumors in vivo! Specific Aim 1; to determine the differences amongptc+/- mouse tumors in their gene expression profiles and their similarities with human medulloblastomas. With gene chips, we will analyze mouse tumors profiles.
Specific Aim 2; to test if NT-3/TrkC signaling induces apoptosis mptc+/- mouse medulloblastomas in vitro. We will stimulateptc+/- mouse tumor cell cultures with NT-3 and compare their response to human tumors.
Specific Aim 3; to test if NT-3/TrkC signaling limits mouse medulloblastoma growth in vivo. We will test if the loss of function (trkC) in vivo yields more aggressive tumor growth, by characterizing the survival of tumors from double mutant trkC+/-ptc+/- mice. We will also test if the gain of function (trkC) in vivo restricts tumor progression by treating intracerebral tumor grafts in nude mice with intratumoral NT-3 infusions. Mouse tumors will be evaluated with gene chips, assays for proliferation and apoptosis, and in vivo magnetic resonance imaging (MRI). These proposed studies will establish the genotype-phenotype correlations in mouse tumors for eventual testing in human medulloblastoma. Ultimately, we hope to identify apoptotic mechanisms in ptc+/- mouse medulloblastomas and develop biologically based therapies more effective and less toxic than current regimens. =ERFORlviANCE SITE(S) (organization, city, state) Laboratories and facilities of the Division of Neuroscience in the John Enders Pediatric Research Building, Children's Hospital, Boston, MA KEY PERSONNEL ========================================Section End===========================================
