MECHANISMS CONTROLLING EXPRESSION OF NEW TUMOR TARGETS

控制新肿瘤靶标表达的机制

• 批准号: 6329076
• 负责人: Manohar Ratnam
• 金额: $ 21.78万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6329076
• 关键词: DNA footprinting; RNase protection assay; cell line; cholecalciferol; complementary DNA; folate; gel mobility shift assay; gene expression; genetic promoter element; messenger RNA; myelogenous leukemia; neoplasm /cancer genetics; neoplastic cell; northern blottings; nucleic acid sequence; polymerase chain reaction; posttranscriptional RNA processing; protein isoforms; receptor expression; reporter genes; retinoids; southern blotting; transcription factor; vitamin receptor; western blottings

DESCRIPTION (Applicant's Abstract): The folate receptor (FR) has been found to be a promising tumor marker and a target for several novel therapeutic approaches in laboratory and in pre-clinical and clinical trials. The applicant's laboratory has contributed substantially to the identification of multiple tissue specific isoforms of the FR and studies of their structure, function, and differential regulation in various malignancies including the establishment of FR type beta as a myeloid differentiation marker and a potential marker for certain myeloid leukemias. The gene structures and the basal promoters for the FR isoforms have been characterized by the applicant's and other laboratories. Preliminary studies show that FR beta is specifically and strikingly upregulated in myeloid leukemia cells by retinoic acid, independent of differentiation. Preliminary studies also indicate that large differences in FR alpha mRNA levels among carcinoma cells occur post-transcriptionally. The applicant proposes to study molecular mechanisms underlying critical regulatory processes in FR expression by (i) identification of putative novel regulatory elements in the FR alpha, beta, and gamma genes that confer their narrow tissue and tumor specificity; (ii) characterization of upstream and downstream molecular events in differentiation- independent retinoid-induced modulation of the FR beta gene in myeloid leukemia cells; and (iii) elucidation of the post-transcriptional mechanisms responsible for the variable expression of FR-alpha among carcinoma cells. All of the above studies with cell lines will be extended to malignant situations in vivo. The proposed studies will resolve key issues of clinical significance in FR regulation and will investigate a promising novel strategy to treat myeloid leukemias refractory to retinoid differentiation therapy. They further promise to reveal novel mechanisms of tissue/tumor specific gene regulation with potential applications in the broad context of future gene therapy strategies.

描述（申请人的摘要）： 叶酸受体（FR）被发现是一种有前途的肿瘤标志物 以及实验室和实验室中几种新型治疗方法的目标 在临床前和临床试验中。申请人实验室拥有 对多种组织的识别做出了重大贡献 FR 的特定亚型及其结构、功能的研究， 和各种恶性肿瘤的差异调节，包括 建立 FR 型 β 作为骨髓分化标记物，以及 某些髓系白血病的潜在标志物。基因结构 FR 亚型的基础启动子已被表征为 申请人的实验室和其他实验室。初步研究表明 FR beta 在髓系白血病中特异性显着上调 细胞由视黄酸形成，与分化无关。初步的 研究还表明 FR α mRNA 水平存在巨大差异 癌细胞之间发生转录后。 申请人提议研究关键的分子机制 FR 表达的调控过程通过 (i) 识别假定的 FR α、β 和 γ 基因中的新调控元件 赋予其狭窄组织和肿瘤特异性； (二) 特征描述 分化过程中的上游和下游分子事件- 髓系中 FR beta 基因的独立视黄醇诱导调节 白血病细胞； (iii) 转录后的阐明 导致 FR-α 可变表达的机制 癌细胞。所有上述细胞系研究都将 扩展到体内恶性情况。 拟议的研究将解决具有临床意义的关键问题 FR监管并将研究一种有前途的新策略 治疗对视黄醇分化疗法难治的骨髓性白血病。 他们进一步承诺揭示组织/肿瘤特异性的新机制 基因调控在广泛的背景下具有潜在的应用 未来的基因治疗策略。