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Abstract

Grant Number:	1R01CA110384-01A1
Project Title:	PKA modulation of hedgehog: mouse medulloblastoma model

PI Information:	Name	Email	Title
	WASCHEK, JAMES A.	jwaschek@mednet.ucla.edu	PROFESSOR

Abstract: DESCRIPTION (provided by applicant): Medulloblastoma is the most common malignant brain tumor in children, accounting for 20-25% of pediatric brain tumors. The survival rate for patients with this tumor is about 50%, however the therapy required to eradicate the tumor in children during brain development results in significant additional morbidity. Overactivty of the sonic hedgehog (Shh) signaling cascade appears to occur at high frequency in these tumors. Thus, animal models with medulloblastoma tumors overactive in this signaling pathway are a potentially valuable resource to investigate the initiation and propagation of these tumors, and can also be used to test potential therapies. This proposal investigates a new mouse model in which sonic hedgehog (Shh) signaling is enhanced in the cells that give rise to medulloblastoma. These mice contain two targeted mutations, one in the gene encoding the Shh receptor/tumor suppressor patched-1 (ptc-1), and other in the gene encoding the secreted neuropeptide PACAP (pituitary adenylyl cyclase activating peptide). PACAP receptors are colocalized in the germinal areas the brain that are thought to give rise to medulloblastoma. It is proposed that PACAP normally inhibits Shh signaling and Shh mitogenic action via protein kinase A (PKA). Preliminary data indicate that ptc-1/PACAP double heterozygous mice have a medulloblastoma incidence of 66% (compared to 15% in ptc-1 mice) with an average onset that is significantly more rapid (16 weeks vs. 28 weeks in ptc-1). In this proposal, we will further characterize this model, and plan to use it along with the derived cell lines to better understand the significance of the PACAP/PKA pathway in medulloblastoma and the mechanism by which PKA interacts with the hedgehog pathway.

Public Health Relevance:
This Public Health Relevance is not available.

Thesaurus Terms:
biological signal transduction, disease /disorder model, enzyme mechanism, gene mutation, medulloblastoma, model design /development, neoplasm /cancer genetics, neuropeptide, neuropeptide receptor, protein kinase A, transcription factor
adenylate cyclase, cerebellum, cyclic AMP, granule cell, molecular oncology, protein kinase inhibitor, protein protein interaction, small interfering RNA, tumor suppressor gene
cell line, embryo /fetus cell culture, genetically modified animal, laboratory mouse, microarray technology, terminal nick end labeling

Institution:	UNIVERSITY OF CALIFORNIA LOS ANGELES
	Office of Research Administration
	LOS ANGELES, CA 90095
Fiscal Year:	2005
Department:	MENTAL RETARDATION RES CENTER
Project Start:	01-APR-2005
Project End:	31-MAR-2010
ICD:	NATIONAL CANCER INSTITUTE
IRG:	CG

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