CITED1 nuclear localization and its role in Wilms' tumor pathogenesis

本建议书概述了从指导阶段(K99)到独立阶段(Roo)的过渡 获得独立奖的途径、CITED1核定位及其在肾母细胞瘤发病机制中的作用。在……里面 最初的指导阶段。洛文博士已经表现出了必要的科学独立性准备。 罗文博士秉承原来K99建议书中勾勒的学习目标和职业发展计划 在肾脏和肝脏胚胎学领域形成了专门的专业知识，并应用了这些 他研究胚胎恶性肿瘤、肾母细胞瘤和肝母细胞瘤的技术。卢韦恩博士已经 与他鼓舞人心的导师Mark de Caestecker博士密切合作，在 发育与癌症生物学。这一背景将很好地帮助洛韦德博士，因为他将继续研究 胚胎肿瘤发生的奥秘是器官分化失调和器官衰竭的模型 成熟。重要的是，在这20个月的严格指导中。洛韦恩博士在他的 检测转录激活子异常亚细胞转运的功能意义的研究 CITED1认为核浓缩在体外是致病的，作为CITED1核输出信号的突变 结果在非锚定生长试验中增加集落形成，增强Wilms‘s肿瘤细胞 侵袭性和增加增殖性反应。这些研究将很快扩展到体内 异种移植模型，并将使用一种令人兴奋的新型Wilms肿瘤细胞系进一步验证 洛韦德博士和NCI的一名合作者已经在这一阶段建立了合作关系。洛韦恩博士又做了一些补充 其原理研究的进展旨在阐明CITED1的核浓缩调控机制 Wilms‘s瘤使用蛋白质组学方法确定作为穿梭伴侣或 保留因子，同时还使用基因表达阵列来确定CITEDI激活的潜在靶点。 关于他的职业发展计划。洛文博士已经完成了开发和研究的课程 癌症生物学，负责任的研究和AACR研讨会致力于从 我要去领奖了。洛韦恩博士已经获得了自己的研究空间，完全独立于他的导师，而且 这个实验室设备齐全，可以完成他剩余的研究目标，这些目标没有改变。作为进一步的 作为独立调查人员的准备证据，洛文博士在2010年2月向 NCI将研究Wilms肿瘤发病率和行为的种族差异的生物学基础，这也将 包括一个多机构合作的全球卫生倡议，研究处于危险之中的肯尼亚儿童。最后， 洛文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Wilms肿瘤发生的调控机制，进一步证明他已经准备好了 为了科学独立。目前的Roo提案总结了洛韦德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和获得R01资金的时间表。

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. Loworn has shown the necessary readiness for scientific independence Adhering to the study aims and career development plan outlined in the original K99 proposal, Dr. Loworn has developed specific expertise in the areas of kidney and liver embryology and has applied these techniques to his studies ofthe embryonal malignancies, Wilms' tumor and hepatoblastoma. Dr. Loworn 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. Loworn 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. Loworn 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. Loworn and an NCi collaborator have established during this phase. Dr. Loworn has made additionai 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. Loworn has completed course work in developmental and cancer biology, the responsible conduct of research and an AACR symposium devoted to transitioning from K to ROl awards. Dr. Loworn 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. Loworn 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. Loworn'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. Loworn's research progress to date and outlines his plan to complete his existing study aims and his timeline to secure R01 funding.