MEHARRY RCMI PROGRAM IN WOMEN'S HEALTH RESEARCH

MEHARRY RCMI 女性健康研究项目

• 批准号: 7118799
• 负责人: James Garfield Townsel
• 金额: $ 220.7万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118799
• 关键词: MEHARRY; RCMI; PROGRAM; WOMEN; HEALTH

EXCEED THE SPACE PROVIDED. Ovarian cancer is the leadingcause of death among gynecologic cancers in the United States. The prostaglandin (PG) pathway mediated by cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes is implicated in ovulation and has been suggested as a potential factor in the etiology of ovarian cancer. Preliminary Data: We have utilized cDNA microarrays to compare normal ovarian tissue samples to ovarian carcinomas, and through this process have shown expression levels of COX-1 to be more than 2-fold higher in the cancers. Data published by our collaborators similarly demonstrates that COX-1, not COX-2, is highly expressed in ovarian malignancies. Hypothesis and Aims: The long-range goal of this research is to determine the specific contributions of COX-1 to ovarian carcinogenesis. We hypothesize that in ovarian cancers, COX-1 induces PGE2 production, which targets phosphatidylinositol3 kinase/protein kinase B (PI3K/AKT) signaling and components of this pathway that are involved in tumor growth and progression. We propose the use of custom-made tissue arrays for immunohistochemistry(IHC) staining to measure expression levels of COX-1, COX-2 and molecular markers associated with PI3K: phosphorylated AKT (pAKT), hypoxia induced factor (HIF-la) and vascular endothelial growth factor (VEGF). Parallel in vitro experiments will be performed to further evaluate COX-1 function by treating a COX-1 expressing cell line, OVCAR3, with a selective COX-1 inhibitor,SC-560. We will measure PGE2 metabolism, cell growth, apoptosis, migrationand invasion, as well as expression levels of PI3K, pAKT, HIF-la and VEGF. We will also utilize cDNA microarrays to generate gene profiles that are associated with COX-1. Significance: If we determine that COX-1 is indeed a prominent factor in rumor progression in ovarian cancer, this research may provide the basis for its future use as a biomarker and target for therapy in the management of this deadly disease.

超出空间 提供了 卵巢癌是美国妇科癌症中死亡的主要原因。前列腺素（PG） 由环氧合酶-1（考克斯-1）和环氧合酶-2（考克斯-2）酶介导的途径与排卵有关 并被认为是卵巢癌病因学中的一个潜在因素。初步数据：我们利用 cDNA微阵列比较正常卵巢组织样本卵巢癌，并通过这一过程， 显示癌症中考克斯-1的表达水平高出2倍以上。我们的合作者发布的数据 类似地证实了考克斯-1而不是考克斯-2在卵巢恶性肿瘤中高度表达。假设和目标： 本研究的长期目标是确定考克斯-1在卵巢癌发生中的具体作用。我们 假设在卵巢癌中，考克斯-1诱导靶向磷脂酰肌醇3的PGE 2产生 激酶/蛋白激酶B（PI 3 K/AKT）信号传导和参与肿瘤生长的该途径的组分， 进展我们建议使用定制的组织阵列进行免疫组织化学（IHC）染色， 考克斯-1、考克斯-2和与PI 3 K相关的分子标记物：磷酸化AKT（pAKT）的表达水平， 缺氧诱导因子（HIF-1 α）和血管内皮生长因子（VEGF）。平行体外实验将 通过用选择性抗肿瘤药物处理表达考克斯-1的细胞系OVCAR 3，进一步评价考克斯-1的功能。 考克斯-1抑制剂，SC-560。我们还将检测PGE 2代谢、细胞生长、凋亡、迁移和侵袭， 作为PI 3 K、pAKT、HIF-1 α和VEGF的表达水平。我们还将利用cDNA微阵列来产生基因 与考克斯-1相关的特征。意义：如果我们确定考克斯-1确实是一个突出的因素， 卵巢癌的肿瘤进展，这项研究可能提供了基础，其未来的用途作为一个生物标志物和目标， 治疗这种致命疾病的方法。