This Program Project Grant involves a concerted and interactive effort in an ongoing program to impact on benign prostatic hyperplasia (BPH) that is one of the least studied but most common and expensive medical problems in the U.S. male. These investigators have been working together for over a decade on these problems. Project 1 has developed a new noninvasive, high resolution MRI system that permits the quantitative assessment of the histology and zones of the prostate. This system will monitor prostate growth in the Baltimore Longitudinal Aging Study, which is the largest and most thorough continuing studies of 1,500 males over a 25 year period. Rates of change of serum prostatic specific antigen (PSA) and steroid profiles will be included to develop a staging and grading system that will not only shed insight on the natural history of this disease but will have important ramifications in therapeutic decisions. Project 1 is designed to provide a molecular study of familial BPH where a segregation pattern is suggestive of Mendelian inheritance. These studies involve over 10,000 monozygotic and dizygotic twins who served in the military in World War II and are now being monitored in a medical followup study, as well as over 4,000 men with BPH who have been studied as part of the Merck Proscar trial. Linkage analysis on pedigree data will be performed and a general genome screen will be performed on 300 polymorphic DNA markers, as well as a series of suppressor genes. Project 2 will study the formation of DNA adducts and alterations in DNA methylation patterns and changes in genome stability. Project 3 will contribute to the question of why abnormal growth of the prostate is so common and yet is a rare event or does not exist in other sex accessory tissues. This is believed to be due to the 3- dimensional organization of the DNA within the tissue that is defined by the nuclear matrix which contains tissue specific proteins that are altered in the development of BPH in both man and dog. Project 4 provides a new system for quantitating stem cells and assessing the rates of cell growth and cell death in human prostate tissues. Project 5 has developed a new model for producing outflow obstruction in the dog that permits monitoring temporal development of bladder pathology to define points of irreversibility. Project 6 seeks the elucidation of the role and regulation of nitric oxide as a neurotransmitter in producing prostate tone and relaxation. Most importantly, over the last 5 years we have developed the first evidence in longitudinal studies that BPH can be prevented during aging in the dog by physiologically clamping the serum androgen and estrogen levels at normal values.
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