CELL/CELL INTERACTION AND PROSTATE GROWTH

细胞/细胞相互作用和前列腺生长

• 批准号: 6177820
• 负责人: JOHN Tod ISAACS
• 金额: $ 20.04万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-07 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177820
• 关键词: androgen receptor; animal breeding; athymic mouse; benign prostate hyperplasia; cell cell interaction; cell death; cell growth regulation; cell line; cell proliferation; dihydrotestosterone; hormone regulation /control mechanism; human subject; human tissue; laboratory mouse; male; neoplastic growth; polymerase chain reaction; prostate neoplasms; testosterone; transfection; xenotransplantation

DESCRIPTION While significant progress has been made upon defining the molecular steps in androgen action in prostatic tissue, there are a series of major controversies which have not been resolved particularly with regard to the importance of cell/cell interaction in such androgen action. One of the most significant of these controversies involves whether androgen action in the normal vs neoplastic prostate involves an intracrine, autocrine, or paracrine pathway. Since prostatic glandular cells express the androgen receptor, originally it was assumed that androgen action involves a completely intracellular (i.e., intracrine) pathway. In this intracrine model, once testosterone is converted to DHT within glandular cells it binds to the androgen receptor and the binding of the dihydrotestosterone (DHT) androgen receptor complex to androgen response elements within the promoter region of specific androgen responsive genes leads to the production of specific mRNAs whose expression results in proteins retained within the glandular cell itself to generate specific signals either to maintain secretory function and suppress programmed death to proliferate. Recent studies have questioned whether androgens act directly within the prostatic glandular cells themselves. These studies suggest that the critical DHT-androgen receptor interactions actually occur in prostatic stromal cells inducing these stromal cells to synthesize and release soluble factors whose functions are to regulate the balance between proliferation and death of the prostatic glandular cells. Since during the development of both BPH and prostate cancer, this balance is abnormally disrupted, there is a critical need to resolve the role of stromal cells in androgen regulated normal and abnormal growth of the prostate. This is particularly critical since there is experimental data supporting the idea that during prostatic neoplastic progression, there is a shift from the normal paracrine to an autocrine or intracrine mechanism of androgen action. Resolving this issue is critical since depending on the answer, the choice of theoretical, as well as practical targets and/or methods to prevent the development of these prostatic disorders would be profoundly different. Based upon this realization, the present RFA specifically has called for applications to study cell/cell interaction and prostate growth. In the present application, a series of unique xenograft and molecular biologic methods will be used to clarify the role of stromal cell interactions in the androgen regulation of the in vivo growth of normal, BPH, and malignant human prostate tissues.

描述 虽然在定义分子步骤方面已经取得了重大进展 雄激素在前列腺组织中的作用，有一系列主要的作用 尚未解决的争议，特别是关于 细胞/细胞相互作用在这种雄激素作用中的重要性。 中的一个 其中最重要的争议涉及雄激素是否在 正常前列腺与肿瘤性前列腺涉及内分泌、自分泌或 旁分泌途径。 由于前列腺细胞表达雄激素 受体，最初认为雄激素作用涉及 完全细胞内（即内分泌）途径。 在这个分泌内 模型中，一旦睾酮在腺细胞内转化为 DHT，它就会结合 雄激素受体和二氢睾酮 (DHT) 的结合 启动子内雄激素受体复合物与雄激素反应元件 特定雄激素反应基因的区域导致产生 特定的 mRNA 的表达导致蛋白质保留在 腺细胞本身产生特定信号或者维持 分泌功能并抑制程序性死亡增殖。 最近的 研究质疑雄激素是否直接作用于前列腺 腺细胞本身。 这些研究表明关键 DHT-雄激素受体相互作用实际上发生在前列腺基质细胞中 诱导这些基质细胞合成并释放可溶性因子， 其功能是调节细胞增殖与死亡之间的平衡 前列腺细胞。 在 BPH 和 BPH 的发展过程中 前列腺癌，这种平衡被异常破坏，有一个关键 需要解决基质细胞在雄激素调节正常和 前列腺异常生长。 这一点尤其重要，因为 实验数据支持这样的观点：在前列腺肿瘤期间 进展，从正常旁分泌转变为自分泌或 雄激素作用的内分泌机制。 解决这个问题至关重要 因为这取决于答案、理论的选择以及 防止这些问题发展的实际目标和/或方法 前列腺疾病则截然不同。 基于此 实现，目前的 RFA 特别呼吁申请 研究细胞/细胞相互作用和前列腺生长。 在现在 应用，一系列独特的异种移植和分子生物学方法 将用于阐明基质细胞相互作用在 雄激素对正常、BPH 和恶性肿瘤体内生长的调节 人类前列腺组织。