ENDOTHELIN B RECEPTOR AND PROSTATE CANCER

描述（申请人描述）： 前列腺癌是美国癌症死亡的第二大常见原因。 男人 有效治疗晚期疾病需要更好地了解 前列腺癌肿瘤生物学的研究。 乔尔B医生。纳尔逊渴望成为 独立研究产生的见解，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）支持一个优秀的临床医生的发展 研究科学家，和2）研究内皮素B受体（ET B）作为 潜在的人类前列腺癌肿瘤抑制因子。 这项指导性研究 奖项将提供乔尔博士B。纳尔逊与一辆车的训练中， 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，奖项赞助商。 良性前列腺增生症的主要内皮素受体 前列腺上皮细胞，ETB在前列腺癌中大大减少， 与CpG二核苷酸序列的体细胞高甲基化相关， 在所研究的前列腺癌中，ETB基因的5 '区域超过60%。 ETB受体具有独特的功能，包括配体清除， 内皮素-1分泌的抑制和反调节的激活 途径。 这个项目的目的是调查的假设，损失 ETB在前列腺癌中的功能直接促进了癌的发生， 进展和发病率。 为了检验ETB的丢失 表达是前列腺癌发生的关键步骤，ETB表达 将在前列腺癌细胞系中通过稳定的 转染编码ETB的cDNA构建体。 表达ETB的亚克隆将 评估生长潜力、致瘤性和表型选择。 为了验证前列腺癌中ETB表达缺失导致前列腺癌发生的假设， 局部ET轴失调，ET-1表达和产生的调节 将研究在表达ETB受体的前列腺细胞系中的作用。 到 测试ETB表达的缺失导致 关键ETB介导的第二信使途径，几个信号 将在正常和恶性前列腺组织中研究级联。 到 验证ETB基因可能导致ETB表达缺失的假设 突变，通过原位杂交测定ETB mRNA表达 将结合ETB突变分析。 对此的广泛方法 前列腺癌肿瘤生物学的发展问题将提供一个很好的 培训经验和新颖的见解。

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.