CYCLIN DEPENDENT KINASE INHIBITORS IN BENIGN AND MALIGNANT PROSTATIC DISEASES

我们的研究目标集中在继续刻画 细胞周期蛋白依赖性激酶基因突变和表达模式的改变 抑制物(CKI)在肿瘤发生和肿瘤过程中的作用 前列腺癌的进展。我们的假设是， KIP和INK基因，以及那些影响其编码产物的基因， 对前列腺生长产生选择性优势，并具有侵略性 前列腺癌患者的行为。具体目标概述如下 以下是： 目的#1：确定其发生频率和潜在的临床相关性 影响KIP基因的突变，以及改变的模式 其编码蛋白在良性前列腺增生症中的表达 (BPH)和前列腺癌。我们在前列腺增生症中发现了明显的p27异常 和前列腺癌，支持了BPH不是 癌前病变。此外，前列腺癌显示p27 研究发现，阴性表型在生物学上更具侵略性。我们计划 以验证这些观察结果，并研究p21和p57基因。 目标2：确定突变的比率和可能的临床相关性 产生于墨水基因，以及改变的表达模式 它们的编码产物，在BPH和前列腺癌中。初步数据 揭示了p16表达和p16甲基化的改变模式 启动子是前列腺癌中常见的事件。我们计划延长和 验证这些数据并评估影响的变更的相关性 P18和p19。 目的#3：进一步描述前列腺组织的组织病理学特征。 KIP或墨水功能丧失的动物模型，并产生转基因 使用组织特异性启动子的模型。我们已经设计了长江基建的淘汰赛 小鼠(即P27和Ink4a)。P27 MULL小鼠发育出高细胞前列腺癌 腺体；然而，没有观察到前列腺癌以上。转基因小鼠 将使用Cyclins E或每个D-型融合到大鼠前盆产生 P27或p16存在或缺失时的启动子。一位模特 模仿人类疾病是意料之中的。 目标是将基础和临床研究成果转化为 临床研究，并与奥布莱恩中心和成员合作 在科学界，评估潜在的肿瘤标记物 关联性。

The objective of our research focuses on the continued characterization of mutations and altered expression patterns of cyclin-dependent kinase inhibitors (CKI) as they rate to processes of tumorigenesis and tumor progression in prostate cancer. It is our hypothesis that abnormalities of KIP and INK genes, as well as those that affect their encoded products, produce a selective advantage for prostate growth and an aggressive behavior in prostate cancer patients. The Specific Aims are outlined as follows: Aim #1: To determine the frequency and potential clinical relevance of mutations affecting the KIP genes, as well as altered patterns of expression of their encoded proteins, in benign prostatic hyperplasia (BPH) and prostate carcinoma. We have found distinct p27 anomalies in BPH and prostate tumors, supporting the postulate that BPH is not a premalignant lesion. Moreover, prostatic carcinomas displaying a p27 negative phenotype were found to be biologically more aggressive. We plan to validate these observations and to study p21 and p57 genes. Aim #2: To define the rate and possible clinical relevance of mutations arising in the INK genes, as well as altered patterns of expression of their encoded products, in BPH and prostatic carcinoma. Preliminary data reveals that altered patterns of p16 expression and methylation of he p16 promoter are frequent events in prostate cancer. We plan to extend and validate these data and to assess the relevance of alterations affecting p18 and p19. Aim #3: To further characterize the histopathology of prostatic tissue in animal models for loss of KIP or INK function, and to produce transgenic models using tissue-specific promoters. We have engineered CKI knockout mice (ie, p27 and Ink4a). p27 mull mice develop hyper-cellular prostatic glands; however,over prostate neoplasms are not observed. Transgenic mice will be generated using cyclins E or each D-type fused to the rat probasin promoter in the presence and absence of either p27 or p16. A model mimicking the human disease is expected. The goal is to translated basic and clinical research findings into clinical studies, and to collaborate with the O'Brien Centers and members of the scientific community, evaluating tumor markers of potential relevance.