Investigating roles for transcriptional co-activators Eya2 and Eya3 in normal development and rhabdomyosarcoma

研究转录共激活因子 Eya2 和 Eya3 在正常发育和横纹肌肉瘤中的作用

• 批准号: 9994632
• 负责人: Jenean O'Brien
• 金额: $ 15.73万
• 依托单位: COLLEGE OF ST SCHOLASTICA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9994632
• 关键词: Investigating; roles; transcriptional; co; activators

Project Summary The research objectives in this proposal are aimed at increasing our basic understanding of how Eya2 and Eya3, co-factors to the transcriptional activator Six1, may mimic their embryonic roles as they function in the muscle cancer rhabdomyosarcoma (RMS). With five year survival rates less than 30% and few targeted molecular therapies available, pediatric patients facing this deadly disease depend primarily on surgery and radiation for treatment. Long term effects of these treatments include severe, disabling and life-threatening effects (i.e. secondary tumors), which are experienced by more than 50% of childhood cancer survivors. Therefore, therapies with much lower toxicities, including those currently in development which are directed specifically at Eya-Six1, are of high interest, especially for young patients. However the functions of individual Eya family members in RMS progression, which will be investigated here, may affect whether these targeted therapies are appropriate for RMS patients. Previous studies of Eya proteins have demonstrated that biological context can have diverse effects on their function, as extreme as promoting tumor progression through enhancing cellular immortalization versus participating in tumor suppressive activities such as triggering apoptosis. Bioinformatic analysis of RMS gene expression indicates divergent roles for Eya proteins in this disease in particular, as Eya2 levels are significantly increased while Eya3 levels are significantly decreased in RMS tumors compared to normal muscle controls. This oppositional expression aligns with the dissimilar roles previously observed for these two Eya proteins in normal muscle development, in addition to recent evidence for varied immune roles. As embryonic programs are often usurped by tumor cells, this proposal is focused on investigating whether Eya2 and Eya3 function divergently in normal muscle and immune development and how these diverse roles may contribute to RMS progression by Eya2 versus RMS suppression by Eya3. Zebrafish will be utilized for these studies as CRISPR gene knockout strategies, ease of embryonal investigations and an existing RMS model all align to make this an ideal organism for these experiments. Data collected here has the potential to impact future drug design and expand treatment options for RMS patients.

项目概要 本提案中的研究目标旨在提高我们的基础 了解 Eya2 和 Eya3 作为转录激活因子 Six1 的辅助因子如何 可能会模仿它们在肌肉癌中发挥作用时的胚胎作用 横纹肌肉瘤（RMS）。五年生存率低于 30%，而且很少 可用的靶向分子疗法，面临这种致命疾病的儿科患者 主要依靠手术和放射治疗。这些的长期影响 治疗包括严重、致残和危及生命的影响（即继发性肿瘤）， 超过 50% 的儿童癌症幸存者都经历过这种情况。所以， 毒性低得多的疗法，包括目前正在开发的疗法 专门针对 Eya-Six1 的药物引起了人们的高度兴趣，特别是对于年轻患者而言。 然而，个别 Eya 家族成员在 RMS 进展中的功能，将 在这里进行研究，可能会影响这些靶向治疗是否适合 RMS 患者。先前对 Eya 蛋白的研究表明，生物 环境可能对其功能产生多种影响，最极端的是促进肿瘤 通过增强细胞永生化而不是参与肿瘤来进展 抑制活动，例如触发细胞凋亡。 RMS基因的生物信息分析 表达表明 Eya 蛋白在这种疾病中的不同作用，特别是 Eya2水平显着升高，而Eya3水平显着降低 RMS 肿瘤与正常肌肉对照相比。这种对立的表达方式是一致的 之前在正常情况下观察到这两种 Eya 蛋白具有不同的作用 肌肉发育，以及最近关于不同免疫作用的证据。作为 胚胎程序经常被肿瘤细胞篡夺，该提案的重点是 研究 Eya2 和 Eya3 在正常肌肉和免疫中的功能是否存在差异 Eya2 的开发以及这些不同的角色如何促进 RMS 进展 与 Eya3 的 RMS 抑制相比。斑马鱼将用于这些研究 CRISPR 基因敲除策略、胚胎研究的简易性以及现有的 RMS 模型全部一致，使其成为这些实验的理想生物体。数据 这里收集的信息有可能影响未来的药物设计和扩大治疗范围 RMS 患者的选择。