CITED1 nuclear localization and its role in Wilms' tumor pathogenesis

CITED1核定位及其在肾母细胞瘤发病机制中的作用

• 批准号: 8122503
• 负责人: Harold Newton Lovvorn
• 金额: $ 24.9万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8122503
• 关键词: Nephroblastoma; Nuclear; Pathogenesis; Role

This proposal outlines the transition from the mentored (K99) to the Independent (ROO) phases of the Pathway to Independence Award, CITED1 nuclear localization and its role in Wilms' tumor pathogenesis. In the initial mentored phase. Dr. Lovvorn has shown the necessary readiness for scientific independence Adhering to the study aims and career development plan outlined in the original K99 proposal, Dr. Lovvorn has developed specific expertise in the areas of kidney and liver embryology and has applied these techniques to his studies of the embryonal malignancies, Wilms' tumor and hepatoblastoma. Dr. Lovvorn has worked closely with his Inspiring mentor, Dr. Mark de Caestecker, to acquire this unique skill set in Developmental and Cancer biology. This background will serve Dr. Lovvorn well as he continues to pursue the mysteries of embryonal tumorigenesis as a model of dysregulated organ differentiation and failed organ maturation. Importantly during these twenty months of rigorous mentoring. Dr. Lovvorn has shown in his studies testing the functional significance of aberrant sub-cellular trafficking of the transcriptional activator CITED1 that nuclear enrichment is pathogenic in vitro, as mutation of the CITED1 nuclear export signal results in increased colony formation in anchorage-independent growth assays, enhances Wilms' tumor cell Invasiveness and increases proliferative responses. These studies will soon be extended to an In vivo heterotransplant model and will be validated further using an exciting and novel Wilms' tumor cell line that Dr. Lovvorn and an NCI collaborator have established during this phase. Dr. Lovvorn has made additional progress in his principle study aims to clarify the mechanism regulating nuclear enrichment of CITED1 In Wilms' tumor using a proteomic approach to identify binding partners that function as shuttling chaperones or retention factors, while also using a gene expression array to identify potential targets of CITEDI activation. Regarding his career development plan. Dr. Lovvorn has completed course work in developmental and cancer biology, the responsible conduct of research and an AACR symposium devoted to transitioning from K to R01 awards. Dr. Lovvorn has secured his own research space entirely separate from his mentor, and this laboratory is fully equipped for completing his remaining study aims, which have not changed. As further evidence for readiness as an independent investigator, Dr. Lovvorn submitted in 2/10 an R21 proposal to the NCI to study the biological basis for racial disparities in Wilms' tumor incidence and behavior, which also will include a multi-institutional and collaborative global health initiative studying at-risk Kenyan children. Finally, the continued success of Dr. Lovvorn's research has attracted two post-doctoral research fellows (T32 awardees) who wish to study mechanisms regulating Wilms' tumorigenesis, further attesting to his readiness for scientific independence. The current ROO proposal summarizes Dr. Lovvorn's research progress to date and outlines his plan to complete his existing study aims and his timeline to secure R01 funding.

该提议概述了从指导者（K99）到独立阶段的过渡 独立奖项，引用了1个核定位及其在Wilms肿瘤发病机理中的作用。在 初始指导阶段。 Lovvorn博士表明了对科学独立的必要准备 遵守原始K99提案中概述的研究目标和职业发展计划，Lovvorn博士 已经在肾脏和肝脏胚胎学领域开发了特定的专业知识，并应用了这些专业知识 他对胚胎恶性肿瘤，威尔姆斯的肿瘤和肝母细胞瘤的研究的技术。 Lovvorn博士有 与他的鼓舞人心的导师Mark de Caestecker博士紧密合作，以获得这一独特的技能 发育和癌症生物学。当他继续追求Lovvorn博士时，这种背景将为Lovvorn博士提供服务 胚胎肿瘤发生的奥秘作为器官分化和器官失败的模型 成熟。重要的是，在这20个月的严格指导中。洛夫沃恩博士在他的 研究测试转录激活剂异常亚细胞运输的功能意义 引用1，核富集在体外是致病性的，因为引用的突变1核输出信号 导致在锚固无关生长测定中的菌落形成增加，增强了Wilms的肿瘤细胞 侵入性并增加增殖反应。这些研究很快将扩展到体内 杂移模型，将使用令人兴奋且新颖的Wilms的肿瘤细胞系进一步验证 Lovvorn博士和NCI合作者在此阶段建立了。 Lovvorn博士增加了 他的主要研究进展旨在阐明调节核富集的机制 使用蛋白质组学方法的Wilms的肿瘤来识别绑定伴侣，这些伴侣作为穿梭伴侣或 保留因子，同时还使用基因表达阵列来识别引用激活的潜在靶标。 关于他的职业发展计划。 Lovvorn博士已经完成了发展的课程工作 癌症生物学，负责任的研究和专门从 K至R01奖。 Lovvorn博士已将自己的研究空间与他的导师完全分开， 该实验室有足够的装备来完成其剩余的研究目标，但尚未改变。更远 洛夫沃恩博士在2/10提交了R21提案的证据 NCI研究威尔姆斯肿瘤发生率和行为中种族差异的生物学基础，这也将 包括一项多机构和协作的全球健康计划，研究高危肯尼亚儿童。最后， Lovvorn博士的研究的持续成功吸引了两个博士后研究研究员（T32 获奖者）希望研究调节威尔姆斯肿瘤发生的机制，进一步证明他的准备 为了科学独立。当前的ROO提案总结了Lovvorn博士的研究进度 并概述了他完成现有研究的计划以及获得R01资金的时间表。