ENDOTHELIN B RECEPTOR AND PROSTATE CANCER

描述(申请人的描述)： 前列腺癌是美国第二大癌症死亡原因。 男人。晚期疾病的有效治疗需要更好的理解 前列腺癌肿瘤生物学的研究。乔尔·B·尼尔森博士的职业生涯是 独立研究产生的洞察力导致有用的治疗 治疗前列腺癌。因此，这一相互包容的目标 应用程序是1)支持优秀临床医生的发展 研究科学家，以及2)研究内皮素B受体(ETB)作为 潜在的人类前列腺癌肿瘤抑制因子。这项有指导意义的研究 该奖项将为乔尔·B·纳尔逊博士提供一辆用于 人的分子生物学、信号转导和受体药理学 布雷迪泌尿研究所研究实验室的前列腺癌 约翰霍普金斯大学医学院，在威廉·G。 纳尔逊，获奖赞助商。良性血管病变中主要的内皮素受体 前列腺上皮细胞，前列腺癌患者ETB显著减少， 与CpG二核苷酸序列的体细胞超甲基化相关 在所研究的前列腺癌中，超过60%的人存在ETB基因5‘端区域。 ETB受体具有独特的功能，包括清除配体， 抑制内皮素-1的分泌，激活反向调节 小路。这个项目旨在调查损失的假设 前列腺癌中ETB功能的改变直接导致了癌症的发生， 进展和发病率。来检验ETB损失的假设 表达是前列腺癌发生的关键步骤，ETB表达 将通过稳定的方式在前列腺癌细胞系中重组 ETB编码基因构建体的转基因研究。ETB表达亚克隆将 进行生长潜力、致瘤性和表型选择的评估。 检验前列腺癌中ETB表达缺失导致前列腺癌的假设 局部ET轴去调节，对ET-1表达和产生的调节 在表达ETB受体的前列腺细胞系中将进行研究。至 检验ETB基因表达缺失导致基因缺失的假设 关键的ETB介导的二级信使通路，几个信号 将在正常和恶性前列腺组织中研究级联反应。至 检验ETB基因可能导致ETB表达缺失的假设 突变、ETB基因表达的原位杂交法测定 将与ETB突变分析相结合。解决这一问题的广泛方法 前列腺癌肿瘤生物学中不断发展的问题将提供一个极好的 培训经验和新奇见解。

DESCRIPTION (Applicant's Description): Prostate cancer is the second most common cause of death from cancer in U.S. men. Effective treatment of advanced disease demands a better understanding of prostate cancer tumor biology. Dr. Joel B. Nelson aspires to a career of independent research producing those insights which lead to useful therapy for prostate cancer. Therefore, the mutually inclusive objectives of this application are 1) to support the development of an outstanding clinician research scientist, and 2) to investigate the endothelin B receptor (ETB) as potential human prostate cancer tumor suppressor. This mentored research award will provide Dr. Joel B. Nelson with a vehicle for training in the molecular biology, signal transduction and receptor pharmacology of human prostate cancer at the Brady Urological Institute Research Laboratories of the Johns Hopkins University School of Medicine, under Dr. William G. Nelson, the award sponsor. The predominant endothelin receptor on benign prostate epithelial cells, ETB is greatly reduced in prostate cancer and is associated with somatic hypermethylation of CpG dinucleotide sequences in the 5' region of the ETB gene in over 60% of the prostate cancers studied. The ETB receptor has unique functions, including ligand clearance, inhibition of endothelin-1 secretion, and activation of counterregulatory pathways. This project is designed to investigate the hypothesis that loss of ETB function in prostate cancer directly contributes to carcinogenesis, progression and morbidity. To test the hypothesis that loss of ETB expression is a critical step in prostate carcinogenesis, ETB expression will be reconstituted in prostatic carcinoma cell lines via stable transfection of ETB-encoding cDNA constructs. ETB expressing subclones will be assessed for growth potential, tumorigenicity, and phenotypic selection. To test the hypothesis that loss of ETB expression in prostate cancer causes local ET axis deregulation, the regulation of ET-1 expression and production in prostatic cell lines which express the ETB receptor will be studied. To test the hypothesis that loss of ETB expression results in the loss of critical ETB mediated secondary messenger pathways, several signaling cascades will be studied in both normal and malignant prostate tissues. To test the hypothesis that loss of ETB expression can result from ETB gene mutations, determination of ETB mRNA expression by in situ hybridization will be coupled with ETB mutation analysis. The broad approach to this evolving question in prostate cancer tumor biology will provide an excellent training experience and novel insights.