PROSTATE SPECIFIC MEMBRANE ANTIGEN

前列腺特异性膜抗原

• 批准号: 6648575
• 负责人: Warren D. Heston
• 金额: $ 23.39万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6648575
• 关键词: athymic mouse; clinical research; folate; gene expression; genetic enhancer element; genetic promoter element; genetically modified animals; glutamate receptor; human genetic material tag; human subject; hydrolase; laboratory mouse; membrane proteins; molecular cloning; neoplastic process; prostate neoplasms; prostate specific antigen; protein sequence; protein structure function; tissue /cell culture; transfection; tumor antigens; vitamin metabolism; yeast two hybrid system

Prostate cancer is the most common adult male cancer and it is expected that over 40,000 men will die from this disease this year. Our long term objectives re to identify factors associated with the prostate's unique propensity to develop cancer and to understand their subsequent heterogeneity with respect to malignant potential, as it exhibits a broad gradient of cancers from slowly growing to rapidly progressive bony metastasis and death. We have recently identified an antigen that is highly expressed in prostate cells, Prostate Specific Membrane antigen, PSM. We have identified PSM as a unique folate hydrolase. We have discovered that in cancers the mRNA encoding the membrane from predominates, while in normal cells the form encoding the cytosolic form predominates. The implications of this finding are that the prostate may be a tissue at risk for microenvironmental "folate deficiency", and folate deficiency is associated with increased susceptibility to carcinogenesis. In cancer increasingly folate hydrolase activity resides outside the cell, potentially serving as a means to reacquire folate from polygammaglutamated folate being lost by dying cancer cells. As folate deficiency is associated with limited growth potential the ratio expression of these two majors may contribute to the spectrum of growth potential seen with prostate cancer. We propose to further characterize this unique folate hydrolase and its regulation and to define the folate modulation of growth potential of cells expressing different levels of membrane and cytosolic forms of the protein. We also propose to over- express PSM in the mouse prostate to determine how its expression effects the biology of the prostate in situ. We also propose to generate knockouts of murine PSM to ascertain the importance of its expression at other sites which in the mouse is predominantly the kidney and brain.

前列腺癌是最常见的成年男性癌症， 今年将有超过4万人死于这种疾病我们的长期 目的是确定与前列腺独特的 发展癌症的倾向，并了解他们随后的 恶性潜能的异质性，因为它表现出广泛的 从缓慢生长到快速进展的骨肿瘤梯度 转移和死亡。我们最近发现了一种抗原， 在前列腺细胞中高度表达，前列腺特异性膜抗原， PSM。我们已经确定PSM作为一个独特的叶酸水解酶。我们有 发现，在癌症中， 占主导地位，而在正常细胞中， 占主导地位。这一发现意味着前列腺可能 是微环境“叶酸缺乏症”的风险组织，叶酸 缺乏与增加的致癌易感性有关。 在癌症中，越来越多的叶酸水解酶活性存在于细胞外， 潜在地用作从细胞中重新获得叶酸的手段， 死亡的癌细胞会丢失多γ-谷氨酸叶酸。如叶酸 缺乏与有限的增长潜力有关， 这两个主要的表达可能有助于生长谱 前列腺癌的治疗方法我们建议进一步描述 这种独特的叶酸水解酶及其调节，并定义叶酸 调节表达不同水平的 膜和胞质形式的蛋白质。我们还建议- 在小鼠前列腺中表达PSM，以确定其表达如何影响 前列腺的原位生物学我们还建议产生淘汰赛 以确定其在其他位点表达的重要性 在小鼠中主要是肾脏和大脑。