The ability to prevent and more effectively treat benign and malignant diseases of the prostate requires definition of the specific factors that initiate, promote, and maintain prostatic growth. One of the new and innovative aspects of the present proposal is that the regulation of prostatic growth will be characterized in the human fetus. Investigating the regulation of prostatic growth in animal models that do not spontaneously develop prostatic disease or using established BPH tissue characterized by a doubling time of 20 years may have limited relevance. The hypothesis to be tested is that the development of the human fetal prostate is an androgen dependent event mediated by growth factors that are elaborated by the prostatic mesenchyme.
The specific aims will investigate the biology of prostate growth regulation at the molecular, cellular, and organ level.
The specific aims of this proposal are to demonstrate that: 1) the proliferative activity of the human prostate is intense during fetal development; 2) the fetal prostate is primarily mesenchyme, and the mesenchyme induces glandular formation; 3) fetal proliferation of the human prostate is characterized by temporal and cellular compartmental expression of growth factors and their receptors; 4) steroid hormone receptors are expressed by the mesenchyme during fetal development of the prostate. One hundred twenty whole fetal prostates will be obtained from abortions and stillborns and the entire fetal prostate will be serially step sectioned. The growth rate of the fetal prostate will be determined by calculating prostatic volumes. The proliferative activity of the individual cellular elements of the fetal prostate will be determined by immunohistochemical staining of proliferative cell nuclear antigen (PCNA). The cellular composition of the fetal prostates will be determined using double-immunoenzymatic staining and color assisted computer image analysis. The macroscopic interactions between mesenchyme and epithelium will be examined by three dimensional reconstruction of the fetal prostates. The expression of growth factors (bFGF, KGF, TGFbeta and EGF) and steroid hormone receptors (AR:ER) will be determined using immunohistochemical staining.
The specific aims will be addressed by examining the interrelationships between prostate growth, cellular proliferative activity, cellular composition and expression of growth factors and steroid receptors throughout the development of the fetal prostate. The successful accomplishment of the four specific aims proposed in this grant application are likely to have important implications related to the regulation of prostatic growth and therefore the regulation of prostatic disease.
| Shapiro, E (1999) New concepts on the normal and abnormal developing bladder. Adv Exp Med Biol 462:193-9 |
| Shapiro, E; Seller, M J; Lepor, H et al. (1998) Altered smooth muscle development and innervation in the lower genitourinary and gastrointestinal tract of the male human fetus with myelomeningocele. J Urol 160:1047-53;discussion 1079 |
