The second leading cause of mortality and leading cause of morbidity in males above the age of 40 years is prostatic neoplasia (benign prostatic hyperplasia and adenocarcinoma). Consequently, growth regulation of the prostate has become a major concern to health care professionals and adult males in general. Dr. Daniel Djakiew is applying for a Research Career Development Award in order to allow the candidate to devote his attention to several promising discoveries pertaining to the paracrine regulation of prostate growth. Specifically, the candidate has established a human prostate stromal cell line which secretes a novel neurotrophin (NGF-like peptide) that in turn interacts with low affinity (p75) and high affinity (protrk) NGF receptors to stimulate growth of human prostate epithelia. The short term goals of the candidate are, firstly, to examine the role of steroids in the production of the NGF peptide by stroma cells. This is of significance since the steroidal milieu of the aging male changes in parallel with the increased incidence of prostatic neoplasia.
The second aim of the research plan is to investigate the expression of NGF receptors in benign prostatic hyperplasia (BPH) tissues. Significantly, expression of the p75 NGF receptor is progressively lost in the neoplastic human prostate (BPH and adenocarcinoma). Since the p75 NGF receptor may modulate the activity of the protrk NGF receptor, loss of the p7S NGF receptor may eliminate modulation of the protrk phosphotyrosine kinase, leading to uncontrolled growth of the prostate epithelial cells. In the third specific aim, organ culture techniques will be utilized to investigate the interaction between the NGF peptide and steroids in modulating the balance between cell proliferation and cell death within BPH tissue. The candidate's long term goals are to utilize the findings of this research for the development of to manipulate growth of prostate as a means to modify and/or treat prostatic neoplasia.
|Pflug, B; Djakiew, D (1998) Expression of p75NTR in a human prostate epithelial tumor cell line reduces nerve growth factor-induced cell growth by activation of programmed cell death. Mol Carcinog 23:106-14|
|Dalal, R; Djakiew, D (1997) Molecular characterization of neurotrophin expression and the corresponding tropomyosin receptor kinases (trks) in epithelial and stromal cells of the human prostate. Mol Cell Endocrinol 134:15-22|
|Perez, M; Regan, T; Pflug, B et al. (1997) Loss of low-affinity nerve growth factor receptor during malignant transformation of the human prostate. Prostate 30:274-9|
|Chen, Y; Dicou, E; Djakiew, D (1997) Characterization of nerve growth factor precursor protein expression in rat round spermatids and the trophic effects of nerve growth factor in the maintenance of Sertoli cell viability. Mol Cell Endocrinol 127:129-36|
|Delsite, R; Djakiew, D (1996) Anti-proliferative effect of the kinase inhibitor K252a on human prostatic carcinoma cell lines. J Androl 17:481-90|
|Rajan, R; Vanderslice, R; Kapur, S et al. (1996) Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. Prostate 28:1-9|
|Zolfaghari, A; Djakiew, D (1996) Inhibition of chemomigration of a human prostatic carcinoma cell (TSU-pr1) line by inhibition of epidermal growth factor receptor function. Prostate 28:232-8|
|Wykes, S M; Nelson, J E; Visscher, D W et al. (1995) Coordinate expression of the PRM1, PRM2, and TNP2 multigene locus in human testis. DNA Cell Biol 14:155-61|
|Pflug, B R; Dionne, C; Kaplan, D R et al. (1995) Expression of a Trk high affinity nerve growth factor receptor in the human prostate. Endocrinology 136:262-8|
|Djakiew, D; Pflug, B; Dionne, C et al. (1994) Postnatal expression of nerve growth factor receptors in the rat testis. Biol Reprod 51:214-21|