Abstract

HB-EGF is synthesized as a membrane-anchored juxtacrine growth factor that is shred to released mature HB-EGF, a potent mitogen and chemotactic factor for smooth muscle cells (SMC). HB-EGF activity is mediated by two receptors, ErbB1 and ErbB4. For the most part HB-EGF function in vivo is not well characterized. In the first aim the role of SMC-derived HB-EGF in mediating SMC-EC interactions in blood vessels will be examined in vivo and in vitro. In addition, potential differences in the roles of transmembrane and mature HB-EGF will be analyzed in vivo in transgenic mice.
The second aim i nvolves characterization of novel HB-EGF receptors. One is a 140 kDa protein that has been recently purified and cloned, binds HB-EGF specifically and as a soluble receptor is a specific HB-EGF antagonist. In addition, two novel ErbB4 isoforms, one with an alteration in the juxtamembrane domain that can not be shed and one that lacks the PI3-kinase binding site and can not activate PI3-kinase activity will be further characterized. These proposed studies on HB-EGF function and receptors are significant since HB-EGF has been suggested to contribute to normal physiological responses such as wound healing and pathological processes such as atherosclerosis and pulmonary hypertension.
The Specific Aims of the proposal are: 1. To Investigate the Role of HB-EGF in Blood Vessels including: a) analysis of temporal and spatial HB-EGF promoter-lacZ reporter gene expression in blood vessels of transgenic mice; b) analysis of the effects of HB-EGF on EC-SMC interactions in vitro; c) over- expression of mature, transmembrane and non-cleavable transmembrane forms in the blood vessels of transgenic mice; d) generation of transgenic mice expressing mature HB-EGF only, by deleting the transmembrane and cytoplasmic domains. 2. To Characterize Novel HB-EGF Receptors including: a) Structure and functional analysis of a novel specific 140 kDa HB-EGF receptor; b) characterization of novel alternatively spliced ErbB4 isoforms differing in the juxtamembrane domain and the PI-3K binding domains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM047397-09A1
Application #
6287223
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Somers, Scott D
Project Start
1992-05-01
Project End
2004-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
9
Fiscal Year
2000
Total Cost
$283,143
Indirect Cost

  Institution

Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

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Campbell, C L; Thorsness, P E (1998) Escape of mitochondrial DNA to the nucleus in yme1 yeast is mediated by vacuolar-dependent turnover of abnormal mitochondrial compartments. J Cell Sci 111 ( Pt 16):2455-64
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Elenius, K; Corfas, G; Paul, S et al. (1997) A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester. J Biol Chem 272:26761-8
Soker, S; Gollamudi-Payne, S; Fidder, H et al. (1997) Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165. J Biol Chem 272:31582-8

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