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Abstract

Grant Number:	5R01HD044929-03
Project Title:	Selecting for novel Hedgehog signaling mutations

PI Information:	Name	Email	Title
	DEVOTO, STEPHEN H.	sdevoto@wesleyan.edu	ASSOCIATE PROFESSOR

Abstract: DESCRIPTION (provided by applicant): Our long-term goal is to understand how cell-cell interactions regulate patterning in the development of the fore-brain and the trunk musculoskeletal system. Our labs have demonstrated that Hedgehog signaling is required for both of these processes. Hedgehog signaling is also critical for regulating cell proliferation in humans, activation of Hh signaling is associated with several of the most common cancers. Hedgehog signaling is incompletely understood, and there are very few mutations in model vertebrates that activate Hh signaling. We propose to use a genetic selection protocol to identify large numbers of mutations in a variety of genes in the Hedgehog signaling pathway. We will do this by selecting for mutants in zebrafish that are resistant to low doses of cyclopamine, a drug that specifically inhibits Hedgehog signaling. We expect to find loss of function mutations in the many genes that encode inhibitory regulators of Hedgehog signaling. We also expect to find activating mutations in the many genes that encode activating components of the pathway. Some of these will be new mutations in previously identified components, while some mutations will identify previously unsuspected components in the Hh signaling pathway. All of the mutations will be useful tools for understanding not only the mechanism of Hedgehog signaling, but also the consequences of the activation of Hedgehog signaling on muscle and brain development. In addition, these mutations will identify genes that are likely to play important roles in the development of human cancer.

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

Thesaurus Terms:
biological signal transduction, cell cell interaction, gene mutation
carcinogenesis, forskolin, genetic marker, protein structure, transcription factor, veratrum alkaloid
genetic screening, zebrafish

Institution:	WESLEYAN UNIVERSITY
	237 HIGH STREET
	MIDDLETOWN, CT 06459
Fiscal Year:	2005
Department:	BIOLOGY
Project Start:	01-AUG-2003
Project End:	31-MAY-2007
ICD:	EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
IRG:	ZRG1

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