MOLECULAR PATHWAY TO PROSTATE CANCER

前列腺癌的分子途径

• 批准号: 2098793
• 负责人: Ralph Buttyan
• 金额: $ 21.42万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1995-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2098793
• 关键词: apoptosis; biopsy; carcinogenesis; chromosome deletion; disease /disorder model; epidermal growth factor; fusion gene; gene deletion mutation; gene expression; genetic markers; genetic promoter element; genetically modified animals; growth factor receptors; human papillomavirus; human tissue; immunocytochemistry; laboratory mouse; metastasis; molecular oncology; neoplasm /cancer genetics; neoplastic cell; polymerase chain reaction; postmortem; prostate neoplasms; southern blotting; transforming growth factors; tumor suppressor genes; viral carcinogenesis; apoptosis; biopsy; carcinogenesis; chromosome deletion; disease /disorder model; epidermal growth factor; fusion gene; gene deletion mutation; gene expression; genetic markers; genetic promoter element; genetically modified animals; growth factor receptors; human papillomavirus; human tissue; immunocytochemistry; laboratory mouse; metastasis; molecular oncology; neoplasm /cancer genetics; neoplastic cell; polymerase chain reaction; postmortem; prostate neoplasms; southern blotting; transforming growth factors; tumor suppressor genes; viral carcinogenesis

Prostate cancer is a disease of increasing occurrence and lethality in the American population. Moreover, this disease will have an even greater impact on our public health policies because of the enormous costs that will be involved in treating an indistinguishable patient population having a high percentage of indolent cancers. Our current theories of carcinogenesis would propose that the various developmental stages of prostate cancer might be viewed as a series of genetic lesions, which cooperate to alter the physical behavior of the prostate cell so that it becomes more rapid growing, more metastatic, more resistant to therapies. In the experiments described in this proposal, we will: 1) Survey a large number of primary human prostate cancers for the occurrence of multiple genetic lesions. Molecular analytical techniques will allow us to document the incidence of mutated or deleted p53, deleted nm23, and alterations of genes on the q arm of chromosome 10 in individual cancers. These same tissues will be examined by immunohistochemical procedures to determine whether ERB-1, ERB-2 (neu), or TGF-alpha are overexpressed and whether the rb protein is deficient in Prostate cancer cells. Genetic aberrations will be correlated with the stage of tumor development in an attempt to match sets of mutations with the developmental stage of the prostate cancer. 2) In an attempt to identify the source of genetic instability in prostate cancer, we will additionally survey these same tissues for the presence of human papillomaviruses and whether prostate cancer might overexpress the protein encoded by bcl-2, a suppressor of apoptosis. 3) Create a transgenic mouse model of prostate cancer through which progression must occur with additional genetic mutations. A prostate-specific gene promotor will be utilized to drive intense expression of dominant-mutated p53, papillomavirus or bcl-2 in the prostate gland of transgenic mice. Prostate cancers that develop in these mice will be characterized for coordinate genetic lesions to document the existence of coordinate molecular pathways to prostate cancer.

前列腺癌是一种发生疾病的疾病 美国人口。而且，这种疾病将有更大的 影响我们的公共卫生政策，因为巨额成本 将参与治疗无法区分的患者人群 懒惰的癌症比例很高。 我们目前的理论 致癌作用将提出 前列腺癌可能被视为一系列遗传病变， 合作改变前列腺细胞的身体行为，以便 变得更加快速，转移性，对疗法的耐药性更高。 在本提案中描述的实验中，我们将： 1）调查大量的主要人类前列腺癌为 多种遗传病变的发生。 分子分析技术 将允许我们记录突变或删除的P53的发生率， 删除的NM23，以及在10号染色体Q臂上的基因改变 个体癌症。 这些相同的组织将通过 免疫组织化学程序确定ERB-1，ERB-2（NEU）， 或TGF-α过表达，RB蛋白是否缺乏 前列腺癌细胞。 遗传畸变将与 肿瘤发育的阶段，试图将一组突变与 前列腺癌的发育阶段。 2）试图确定遗传不稳定性的来源 前列腺癌，我们还将调查这些相同的组织的 人乳头瘤病毒的存在以及前列腺癌是否可能 过表达由凋亡抑制剂Bcl-2编码​​的蛋白质。 3）创建一个前列腺癌的转基因小鼠模型 必须在其他基因突变中发生进展。 一个 前列腺特异性基因启动子将被用来驱动强烈 在占主导地位的p53，乳头瘤病毒或bcl-2的表达 转基因小鼠的前列腺。 发展的前列腺癌 这些小鼠将以坐标为遗传病变的特征 记录存在前列腺分子途径的存在 癌症。