Benign and malignant diseases are most common in the human prostate but occur only rarely in the seminal vesicles and not at all in the bulbourethral gland. Well over a one-million fold difference in risk of benign disease between these glands is difficult to understand, particularly since the glands reside within the same individual and have the same inherited genome and similar physiology and exposure to environmental risk factors. We believe the answer to this riddle resides within the molecular basis of tissues specificity. We have reported that the tissue specificity and gene expression of the rat prostate is related to tissue-specific nuclear matrix proteins that appear to organize DNA in a tissue specific three-dimensional structure that dictates the activation of tissue specific genes. In animal models of prostate cancer we have also demonstrated specific changes occurring in these nuclear matrix proteins that characterize malignant transformation. Recently, we reported that in the human prostate with the development of BPH, there is a marked change in the pattern of the nuclear matrix proteins and these changes represent a continuum of changes with additional changes being associated with prostate cancer. While BPH and prostate cancers often develop in different regions of the prostate, they may nevertheless share similar early molecular events in their transformation process. This has certainly been the case in cumulative genetic events where changes in benign lesions are also early events in the development of colon and bladder cancer. We propose to identify and characterize the nuclear matrix proteins and how they change during development of BPH and to study how they may be altered by post- translational modification, with particular emphasis on protein phosphorylation and protein methylation. We have also reported that the extracellular matrix is capable of inducing changes in the composition of the nuclear matrix and that is associated with changes in structure and function of the cell. We will isolate extracellular matrix components from the normal prostate and benign prostatic hyperplasia in both the human and canine and determine how they alter the growth of prostate epithelial cells. The nuclear matrix organizes DNA loop domains and the 3-dimensional higher order chromatin structure, therefore, we are also designing new ways to assess chromatin patterns in the nucleus and how the 3-dimensional organization of the nucleus is altered during development of BPH.
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