The broad, long-term objective of this proposal is to elucidate the mechanism of the growth regulation of basic fibroblast growth factor (bFGF) and its related growth factor int-2 in the development of benign prostatic hyperplasia (BPH). The research proposed here is dedicated to the employment of int-2 transgenic mice as a benign prostate hyperplasia model system to investigate the role of int-2 growth factor in the ontogenesis of BPH in a prostate specific manner. The basic assumption of this proposal is that the development of BPH is due to the deregulated growth factor expression and the pathogenesis of BPH can be reproduced by manipulating the interactions between the cells that exhibit aberrant growth factor production and their surrounding tissues. one major goal of this proposal is to elucidate the molecular mechanism of int-2 induced prostatic hyperplasia and apply this observation to further our understanding of possible mechanisms for bFGF in BPH development. To achieve this goal, we will pursue the following specific aims: (1) Examine the molecular and histopathological effect of int-2 growth factor overexpression on prostatic growth regulation and BPH development. (2) Analyze the mesenchymal-epithelial interaction of BPH development employing transgenic mice tissue recombination. (3) Examine int-2 growth factor overexpression modulated ECM expression in vitro using cells derived from int-2 transgenic mouse prostate. (4) Establish a basic fibroblast growth factor (bFGF) transgenic founder line that employs a bigenic system for prostate specific expression. A recently developed binary system for regulating transgene expression in transgenic mice generation will be employed in the construction of bFGF transgenic mice. The basic experimental design involves the manipulation of hyperplastic prostate growth by interfering with the int-2 growth factor activity so that a measurable phenotypic change can be studied. Analyses of the results obtained from the research proposed here will help us gain more insights into how growth factors from bFGF family modulate the mesenchymal-epithelial interactions as well as their role in the growth control and development of BPH.
| Lu, M L; Sato, M; Cao, B et al. (1996) UV irradiation-induced apoptosis leads to activation of a 36-kDa myelin basic protein kinase in HL-60 cells. Proc Natl Acad Sci U S A 93:8977-82 |
