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.

项目摘要 这项建议中的研究目标旨在增加我们的基础 了解Eya2和Eya3，转录激活因子Six1的辅助因子， 可能会模仿它们在肌肉癌中的胚胎作用 横纹肌肉瘤(RMS)。五年存活率不到30%而且很少 有针对性的分子疗法，面对这种致命疾病的儿科患者 主要依靠手术和放射治疗。这些措施的长期影响 治疗包括严重的、致残的和危及生命的影响(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。因此， 毒性低得多的疗法，包括目前正在开发的那些 特别针对Eya-SIX1，引起了人们的高度兴趣，特别是对年轻患者。 然而，单个Eya家族成员在RMS进程中的功能将 可能会影响这些靶向治疗是否适用于 RMS患者。以前对Eya蛋白的研究已经证明，生物 环境可以对它们的功能产生不同的影响，就像促进肿瘤一样极端 促进细胞永生化与参与肿瘤的研究进展 抑制活动，如触发细胞凋亡。RMS基因的生物信息学分析 表达表明Eya蛋白在这种疾病中的不同作用，特别是 Eya2水平显著升高，而Eya3水平显著降低 RMS肿瘤与正常肌肉对照。这个对立的表达方式与 由于先前观察到的这两种Eya蛋白在正常组织中的不同作用 肌肉发育，除了最近的证据表明不同的免疫作用。AS 胚胎计划经常被肿瘤细胞篡夺，这一提议集中在 Eya2和Eya3在正常肌肉和免疫系统中功能差异的研究 开发以及这些不同的角色如何有助于Eya2的RMS进展 对比Eya3对RMS的抑制。斑马鱼将用于这些研究，如 CRISPR基因敲除策略，胚胎研究的简便性和现有的 RMS模型都是一致的，使它成为这些实验的理想有机体。数据 这里收集的药物有可能影响未来的药物设计和扩大治疗 RMS患者的选择。