The broad and long-term goal of this proposed study is to elucidate the functional role of Epidermal growth factor (EGF) receptor in the alimentary tract. Ethanol is one of the most common noxious agents associated with gastric mucosal injury. EGF is a polypeptide mitogen found in large amounts in salivary duodenal and pancreatic glands and is released into their secretions. EGF is important for maintaining the integrity of the gastric mucosa. EGF exerts its biological activity through binding to a specific receptor located on the cellular membrane. In spite of a great deal of information regarding the functions of EGF in gastroprotection and ulcer healing, no information is available as to the regulation of EGF receptor function in these actions. Preliminary experiments conducted by the Principal Investigator (PI) has demonstrated that ethanol causes differential alteration of the [125I]-EGF binding to the gastric mucosal receptor. This ethanol-related changes of EGF binding activity might be associated with the gastroprotection mediated by the EGF receptor. It is therefore, hypothesized that the up-regulation of EGF receptor in gastric mucosa by the acute treatment of low dose ethanol (10- 100mM) is one of the cytoprotective actions against ethanol. However, the EGF receptor may be desensitized and eventually loses its biological functions by the long term treatment of ethanol.
The Specific Aims are: The First Specific Aim is to test the hypothesis that EGF receptor plays an important role in gastroprotective mechanism: The first part of this specific aim will examine the effect of the same treatment of ethanol on biochemical properties of EGF receptor in stomach. Experiments will be conducted to determine whether ethanol alters: (a) the kinetics of [125I]- EGF binding; (b) the structure of EGF receptor protein; and (c) EGF receptor protein tyrosine kinase (PTK) activity. The second part of this specific aim will investigate the effect of acute treatment of ethanol on EGF receptor-mediated cellular responses, such as: (a) enzyme activity of ornithine decarboxylase (ODC); (b) production of prostaglandin E2 (PGE2); (c) mucin synthesis; and (d) DNA synthesis. Correlation between data obtained from the studies of the receptor's biochemical properties and the EGF-stimulated cellular responses will be evaluated statistically. The Second Specific Aim is to test the hypothesis that continuous treatment of ethanol may cause a time-dependent alteration of EGF receptor in the gastric mucosa. A time course study (1 day to 12 weeks) will be performed to determine when and how the biochemical properties and functions of gastric EGF receptor are altered by the ethanol feeding treatment. Data obtained from this proposed research will provide important information regarding the mechanism by which ethanol ingestion exerts toxicity towards the stomach, and the mechanism by which the mucosal cells protect the stomach against noxious insults during healing process.
| Wang, S L; Feng, J; Wu-Wang, C Y (1997) Time-dependent alteration of epidermal growth factor receptor in rat stomach by ethanol feeding. Toxicol Lett 90:115-23 |
| Wang, S L; Wu-Wang, C Y; Feng, J et al. (1996) Chronic ethanol feeding alters the structure and function of the epidermal growth factor receptor in rat stomach. Alcohol 13:461-6 |
