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.

该提案概述了从指导阶段 (K99) 到独立阶段 (ROO) 的过渡 独立之路奖，CITED1 核定位及其在维尔姆斯肿瘤发病机制中的作用。在 最初的指导阶段。 Lovvorn 博士已表现出科学独立的必要准备 Lovvorn 博士遵循最初 K99 提案中概述的学习目标和职业发展计划 在肾脏和肝脏胚胎学领域发展了特定的专业知识，并应用了这些 技术应用于他对胚胎恶性肿瘤、肾母细胞瘤和肝母细胞瘤的研究。 Lovvorn 博士有 与他的鼓舞人心的导师 Mark de Caestecker 博士密切合作，获得了这一独特的技能 发育和癌症生物学。这一背景将有助于 Lovvorn 博士继续追求 作为器官分化失调和器官衰竭模型的胚胎肿瘤发生的奥秘 成熟。重要的是在这二十个月的严格指导期间。 Lovvorn 博士在他的研究中表明 测试转录激活因子异常亚细胞运输的功能意义的研究 CITED1 认为核富集在体外具有致病性，因为 CITED1 核输出信号的突变 在不依赖贴壁的生长测定中导致集落形成增加，增强肾母细胞瘤细胞 侵袭性并增加增殖反应。这些研究很快将扩展到体内 异种移植模型将使用令人兴奋的新型维尔姆斯肿瘤细胞系进一步验证，该细胞系 Lovvorn 博士和 NCI 合作者在此阶段建立了这一机制。 Lovvorn 博士做了补充 他的原理研究取得进展，旨在阐明 CITED1 核浓缩的调控机制 维尔姆斯氏肿瘤使用蛋白质组学方法来识别充当穿梭伴侣或 保留因子，同时还使用基因表达阵列来识别 CITEDI 激活的潜在目标。 关于他的职业发展规划。 Lovvorn 博士已经完成了发展和 癌症生物学、负责任的研究行为和 AACR 研讨会致力于从 K 至 R01 奖项。 Lovvorn 博士拥有完全独立于导师的研究空间，并且 该实验室完全具备完成他剩余的研究目标的能力，这些目标没有改变。如进一步 作为独立调查员准备就绪的证据，Lovvorn 博士于 2 月 10 日向 NCI 将研究肾母细胞瘤发病率和行为方面种族差异的生物学基础，这也将 包括一项研究高危肯尼亚儿童的多机构合作全球卫生倡议。最后， Lovvorn 博士研究的持续成功吸引了两名博士后研究员 (T32 获奖者）希望研究调节维尔姆斯肿瘤发生的机制，进一步证明他已做好准备 为了科学的独立性。目前的 ROO 提案总结了 Lovvorn 博士迄今为止的研究进展 并概述了他完成现有研究目标的计划以及获得 R01 资金的时间表。