SUPPRESSION OF PROSTATE CANCER

此应用程序的双重用途是请求对 将G.Steven Bova医学博士培养成一名医学科学家，并取得进展 对导致疾病发生的分子事件的理解 前列腺癌。博瓦博士试图以他的背景为基础 病理学家和泌尿外科医生将成为独立调查员 泌尿外科肿瘤学的基础科学。这项研究培训将需要 由威廉·B·艾萨克斯博士赞助，背景为 约翰霍普金斯大学医学院布雷迪泌尿科研究所 医学。 尽管前列腺癌的医学问题很严重， 构成了对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。这个 艾萨克斯博士实验室的主要研究目标是鉴定和克隆 基因，作为基因改变的结果，负责 人类前列腺癌的发生。为此，一种系统的方法 利用分子和细胞生物学技术已经开始 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，频繁的基因丢失 来自染色体8p、10、16q和17p的物质，表明基因 在前列腺癌的发展过程中起重要作用的是 地区。具体目标1是检验肿瘤抑制因子的假设 基因驻留在这些缺失的染色体区域，通过引入正常 8、10、16、17号染色体和其他染色体通过 微细胞转移。杂交细胞的致瘤性将通过以下方法进行检测 注射于裸鼠体内。杂交细胞的运动性和侵袭性 将通过延时视频显微镜进行检测，并在体外进行补充 细胞外基质侵袭实验。的存在和程度 被转移染色体的完整性将通过一种组合来确定 分子和细胞遗传学技术，包括Southern blotting， 分析和原位杂交。具体目标2是提供一个基础 通过识别亚染色体区域进行定位克隆 能够通过比较效果来抑制致瘤表型 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.