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Abstract
Grant Number: 5R01HL067822-05 Project Title: Hedgehog signal modulation in mammalian development
PI Information: Name Title CHUANG, PAO-TIEN pao-tien.chuang@ucsf.edu ASSISTANT PROFESSOR Abstract: DESCRIPTION (provided by applicant): The long-term goal of our studies is to elucidate the molecular mechanisms of cell-cell interactions during vertebrate development. This proposal focuses on the Hedgehog (Hh) signaling-pathway, which plays a key role in many developmental events. Mutations in members of the pathway are associated with the development of cancer, including basal cell carcinoma, the most prevalent cancer in Western countries, and a seemingly unrelated number of human syndromes and malformations, such as holoprosencephaly and polydactyly. Consequently, understanding how a Hh signal is received, transduced and modulated will be critical to understand how cells proliferate, differentiate or survive in response to the Hh signal, as well as how deregulated Hh signaling leads to diseases. These studies will also make it possible to perform prenatal genetic diagnosis and help design rational therapies for treating these Hh signaling-related diseases. Our general strategy is to focus on three membrane proteins, Hedgehog-interacting-protein (Hip), Patched (Ptch) and Smoothened (Smo), essential for transducing/modulating the Hh signal. The overall goals for this proposal are to define the role of Hip and Ptch in mammalian development through genetic analysis; to define the molecular interactions between Hip, Ptch and Smo in transducing/modulating Hh signal; and to identify missing components in the Hh pathway. 1. To define Hip's role in Hedgehog signaling during mammalian development. A genetic approach utilizing transgenic knockout mice will be taken to dissect the distinct and overlapping roles Hip and Ptch play in modulating Hh signaling during mammalian development. 2. To elucidate the molecular interactions between the three known components of the Hh signaling pathway, Hip, Ptch and Smo, in transducing/modulating the Hh signal. Biochemical and cell culture approaches will be taken to investigate the molecular interactions between Hip, Ptch and Smo in transducing/modulating the Hh signal. 3. To use Hh-responsive cell lines, in combination with expression cloning and candidate gene strategies, to identify missing components in the Hh signaling pathway.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
biological signal transduction, cell cell interaction, developmental genetics, mammalian embryology, membrane protein
cell growth regulation, protein protein interaction
cell line, expression cloning, gene targeting, genetically modified animal, laboratory mouse
Institution: UNIVERSITY OF CALIFORNIA SAN FRANCISCO 3333 California St., Ste 315 SAN FRANCISCO, CA 941430962 Fiscal Year: 2005 Department: CARDIOVASCULAR RESEARCH INST (CVRI) Project Start: 01-JUL-2001 Project End: 31-MAR-2007 ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE IRG: CDF