BENIGN PROSTATIC HYPERPLASIA-DEVELOPMENTAL APPROACH

良性前列腺增生的发展方法

• 批准号: 3483628
• 负责人: GERALD R CUNHA
• 金额: $ 22.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-09-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3483628
• 关键词: DNA replication; adenocarcinoma; androgens; athymic mouse; autoradiography; cell cell interaction; cell differentiation; connective tissue stroma; embryo /fetus; epithelium; female; gel electrophoresis; genetic manipulation; growth /development; growth factor; histochemistry /cytochemistry; hormone inhibitor; hormone receptor; hormone regulation /control mechanism; hormone related neoplasm /cancer; human tissue; immunocytochemistry; laboratory mouse; laboratory rat; male castration; mesenchyme; monoclonal antibody; neoplastic growth; prostate; prostate preneoplastic state; radiotracer; steroid hormone; tissue /cell culture

The proposed research project is focused upon the following areas of prostatic development all of which have relevance to proliferative diseases of the prostate such as benign prostatic hyperplasia and prostatic adenocarcinoma: (1) Analysis of mesenchymal differentiation during prostatic development; (2) Analysis of prostatic epithelial stem cells; (3) Analysis of regional heterogeneity within the normal and abnormal prostate; (4) Analysis of androgen-dependent ductal branching morphogenesis; (5) Analysis of epithelial-stromal interactions in hormonal imprinting leading to prostatic pathogenesis; and (6) Analysis of the mechanism of mesenchyme-induced regulation of epithelial proliferation. Mesenchymal differentiation and the emergence of smooth muscle cells during normal and abnormal prostatic development will be studied by morphometry and immunocytochemistry. Proliferative activity of urogenital sinus mesenchyme and the localization of extracellular matrix components in the mesenchyme will be assessed by autoradiography and immunocytochemistry. Prostatic epithelial stem cells will be studied by grafting tissue recombinants composed of urogenital sinus mesenchyme (UGM) and small fragments of prostate ducts containing 50 to 500 epithelial cells and determining their proliferative potential. Regional heterogeneity within the prostate will be assessed morphologically by light and electron microscopy, 3H-thymidine autoradiography (ARG), 3H-DHT ARG, and by immunocytochemistry of secretory proteins. Particular attention will be focused upon whether differences in biological activity correlate with androgen receptor activity. A new in vitro model of androgen-induced branching morphogenesis will be pursued utilizing cultures of bulbourethral glands (BUGs) growing in serum-free medium. Cell lineage studies will follow the descendents of single cells microinjected with non-toxic vital tracer dyes. Branching morphogenesis in the developing BUG will be examined specifically to assess the role of extracellular matrix components by histochemistry, immunocytochemistry, and ARG. The role of mesenchymal-epithelial interactions will be examined during the expression of abnormal prostatic epithelial development and growth elicited by neonatal imprinting with exogenous estrogen. Finally, the mechanism of mesenchymal regulation of epithelial proliferation in the BUG will be assessed in transfilter assemblies in a serum-free in vitro system to determine whether diffusible mediators are involved. Ultimately, mesenchymal cell conditioned medium experiments are planned.

拟议的研究项目集中在以下领域 前列腺发展所有与增生性疾病有关 前列腺，例如良性前列腺增生和前列腺 腺癌：（1）间充质分化的分析 前列腺发展； （2）前列腺上皮干细胞的分析； （3） 正常和异常前列腺内的区域异质性分析； （4）分析雄激素依赖性导管分支形态发生； （5） 荷尔蒙印记领导中的上皮 - 层相互作用的分析 前列腺发病机理； （6）分析机制 间充质诱导的上皮增殖调节。 间充质 在正常和 异常前列腺发育将通过形态计量学研究和 免疫细胞化学。 泌尿生殖器窦间充质的增殖活性 以及细胞外基质组件在间充质中的定位 将通过放射自显影和免疫细胞化学评估。 前列腺 将通过接枝组织重组来研究上皮干细胞 由泌尿生殖器窦间充质（UGM）和小片段组成 前列腺管有50至500个上皮细胞并确定其 增殖潜力。 前列腺内的区域异质性 通过光和电子显微镜，3H-胸腺苷进行形态学评估 自显影（ARG），3H-DHT ARG，并通过分泌的免疫细胞化学 蛋白质。 特别关注 生物学活性与雄激素受体活性相关。 一个新的 将追求雄激素诱导的分支形态发生的体外模型 利用囊状腺体培养物（虫）在无血清中生长 中等的。 细胞谱系研究将遵循单细胞的后代 对无毒的重要示踪剂染料进行了显微注射。 分支形态发生 将专门检查开发错误以评估 细胞外基质组件通过组织化学，免疫细胞化学和 arg。 将检查间质上皮相互作用的作用 在表达异常上皮发育和 新生儿印在外源性雌激素上引起的生长。 最后， 间质调节上皮增殖的机制 将在不含血清的体外评估中的虫子。 确定是否涉及扩散介质的系统。 最终， 计划进行间充质细胞调节培养基实验。