SUPPRESSION OF PROSTATE CANCER

此应用程序的双重目的是请求支持 训练G。Steven Bova医学博士作为一名医学科学家， 了解导致发展的分子事件 前列腺癌博瓦博士寻求建立在他的背景， 病理学家和泌尿外科医生将成为独立研究者， 泌尿肿瘤学的基础科学。 这项研究培训将采取 由威廉B赞助。艾萨克斯博士，背景下 约翰霍普金斯大学布雷迪泌尿学研究所 药 尽管前列腺癌是一个严重的医学问题， 构成，对负责的分子事件的基本理解 这种疾病的发生和发展仍然难以捉摸。的 艾萨克斯博士实验室的主要研究目标是识别和克隆 这些基因，作为基因改变的结果， 人前列腺癌发生为此，采取系统的办法， 已经开始利用分子和细胞生物学技术， 分析人类前列腺癌的分子遗传学方面。初步 Bova博士和其他人的研究表明， 来自染色体8p，10，16q和17p的材料，表明基因 前列腺癌的发生发展过程中， 地区 具体目标1是检验肿瘤抑制因子 基因通过引入正常的 染色体8，10，16，17和其他人前列腺癌细胞， 微细胞转移杂交细胞的致瘤性将通过 裸鼠皮下注射。杂交细胞的运动性和侵袭潜力 将通过延时视频显微镜进行测定，并辅以体外 细胞外基质侵袭的测定。 的存在和程度 转移的染色体的完整性将由一种组合来确定， 分子和细胞遗传学技术，包括Southern印迹，PCR 分析和原位杂交。 具体目标2是提供一个基础 通过鉴定亚染色体区域进行定位克隆 通过比较其效果， 将完整和部分缺失的染色体转移到野生型 细胞这些研究将提供第一个功能性证据， 失活的肿瘤抑制基因的存在和定位 在人类前列腺癌中。

The dual purpose of this application is to request support for the training of G. Steven Bova M.D. as a medical scientist, and to advance understanding of the molecular events leading to the development of prostate Cancer. Dr. Bova seeks to build upon his background as pathologist and urologic surgeon to become an independent investigator in the basic science of urologic oncology. This research training would take place under the sponsorship of William B. Isaacs Ph.D., in the setting of the Brady Urologic Institute of The Johns Hopkins University School of Medicine. Despite the magnitude of the medical problem which prostate cancer constitutes, a basic understanding of the molecular events responsible for the initiation and progression of this disease remains elusive. The primary research goal of Dr. Isaacs' laboratory is to identify and clone the genes which, as a result of genetic alteration, are responsible for human prostate carcinogenesis. To this end, a systematic approach utilizing molecular and cell biology techniques has been initiated to analyze molecular genetic aspects of human prostate cancer. Preliminary studies by Dr. Bova and others have demonstrated frequent loss of genetic material from chromosomes 8p, 10, 16q, and 17p, suggesting that genes important in the development of prostate cancer are located in these regions. Specific aim 1 is to test the hypothesis that tumor suppressor genes reside in these deleted chromosomal regions by introducing normal chromosomes 8, 10, 16, 17 and others into human prostate cancer cells via microcell transfer. Tumorigenicity of hybrid cells will be assayed by injection in nude mice. Motility and invasive potential of hybrid cells will be assayed by time-lapse videomicroscopy, complemented by in vitro assays of extracellular matrix invasion. The presence and degree of intactness of transferred chromosomes will be determined by a combination of molecular and cytogenetic techniques, including Southern blotting, PCR analysis, and in situ hybridization. Specific aim 2 is to provide a base for positional cloning efforts by identifying subchromosomal regions capable of suppressing the tumorigenic phenotype by comparing the effect of transfer of intact and partially deleted chromosomes into wild type cells. These studies will provide the first functional evidence for the existence and location of tumor suppressor genes which become inactivated in human prostate cancer.