PROSTATE CELL STRUCTURE AND FUNCTION IN BPH

良性和恶性疾病在人类前列腺中最常见，但 仅在精囊中很少发生，在精囊中根本不发生 球尿道腺。患病风险相差超过一百万倍 这些腺体之间的良性疾病很难理解， 特别是因为腺体驻留在同一个个体内并具有 相同的遗传基因组相似的生理和暴露在 环境风险因素。我们相信这个谜题的答案就在 在分子基础上的组织特异性。我们已经报道了 大鼠前列腺的组织特异性与基因表达相关 到组织特异的核基质蛋白，这些蛋白似乎在 一种组织特有的三维结构，它指示着激活 组织特异性基因。在前列腺癌的动物模型中，我们也有 显示了这些核基质蛋白中发生的特定变化 这是恶性转化的特征。最近，我们报道了在 人类前列腺随着BPH的发展，有一个明显的变化 核基质蛋白的模式和这些变化代表了一种 变化的连续体，与前列腺相关的其他变化 癌症。而前列腺增生症和前列腺癌通常发生在不同的地区 尽管如此，它们可能会分享相似的早期分子事件 在他们的转变过程中。情况肯定是这样的 良性病变的变化也是早期的累积遗传事件 结肠癌和膀胱癌发展中的事件。我们建议 识别和表征核基质蛋白及其变化方式 在良性前列腺增生症的发展过程中，并研究它们可能如何改变后 翻译修饰，特别强调蛋白质 磷酸化和蛋白质甲基化。我们还报道说， 细胞外基质能够诱导血管内皮细胞成分的改变 核基质，它与结构的变化和 细胞的功能。我们将分离细胞外基质成分 正常前列腺和良性前列腺增生症的临床研究 并确定它们如何改变前列腺上皮细胞的生长 细胞。核基质组织DNA环结构域和三维 高阶染色质结构，因此我们也在设计新的方法 来评估细胞核中的染色质模式以及三维 在良性前列腺增生症的发展过程中，细胞核的组织发生了变化。

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.