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: 8309471
• 负责人: Harold Newton Lovvorn
• 金额: $ 24.15万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309471
• 关键词: Adverse event; American Association of Cancer Research; Anchorage-Independent Growth; Area; Award; Behavior; Binding; Biological; Biological Assay; Cancer Biology; Cell Nucleus; Cell Survival; Child; Cytosol; Development; Development Plans; Developmental Biology; Embryo; Embryology; Event; Fetal Kidney; Funding; Future; Gatekeeping; Gene Expression; Genes; Hepatoblastoma; Histologic; Human; Image; In Vitro; Incidence; Instruction; Kidney; Knowledge; Laboratories; Liver; Malignant Neoplasms; Mentors; Modeling; Molecular Chaperones; Mutation; Nephroblastoma; Nuclear; Nuclear Export; Oncogenes; Oncogenic; Organ; Pathogenesis; Pathway interactions; Patients; Peptides; Phase; Play; Point Mutation; Postdoctoral Fellow; Property; Proteomics; Publishing; Readiness; Reporting; Research; Research Personnel; Rhabdomyosarcoma; Risk; Role; Sampling; Secure; Signal Transduction; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stem cells; Techniques; Testing; TimeLine; Tissues; Transcription Coactivator; Tumor Cell Line; Work; base; career development; global health; in vivo; neoplastic cell; nephrogenesis; novel; novel marker; overexpression; response; responsible research conduct; self-renewal; skills; stem cell population; success; symposium; trafficking; transcription factor; tumor; tumorigenesis

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.

本建议概述了从辅导（K99）到独立（ROO）阶段的过渡， Pathway to Independence Award，CITED 1核定位及其在Wilms肿瘤发病机制中的作用。在 第一个指导阶段。洛沃恩博士已经为科学独立做好了必要的准备 坚持在最初的K99提案中概述的研究目标和职业发展计划，Loworn博士 在肾脏和肝脏胚胎学领域发展了特定的专业知识，并将这些知识应用于 他在胚胎性恶性肿瘤、肾母细胞瘤和肝母细胞瘤的研究中运用了多种技术。洛沃恩医生 与他的导师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。这一背景将有助于洛沃恩博士继续追求 胚胎肿瘤发生的奥秘作为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。洛沃恩医生在他的 测试转录激活因子的异常亚细胞运输的功能意义的研究 CITED 1认为核富集是体外致病性的，作为突变的CITED 1核输出信号 在非贴壁依赖性生长测定中导致集落形成增加，增强Wilms肿瘤细胞 并增加增殖反应。这些研究将很快扩展到体内 将使用一种令人兴奋的新的Wilms肿瘤细胞系进一步验证，该细胞系 博士Loworn和NCi合作者在此阶段建立了。洛恩医生还在 他的原则性研究取得了进展，目的是澄清CITED 1的核浓缩调节机制。 使用蛋白质组学方法鉴定作为穿梭分子伴侣或 保留因子，同时还使用基因表达阵列来鉴定CITEDI激活的潜在靶点。 关于他的职业发展计划。Loworn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 to Rol奖项Loworn博士已经获得了自己的研究空间，与他的导师完全分开， 该实验室完全有能力完成他的剩余研究目标，这些目标没有改变。如进一步 作为一名独立调查员的准备证据，Loworn博士在2/10向 NCi研究肾母细胞瘤发病率和行为种族差异的生物学基础，这也将 包括一项多机构和协作性全球卫生倡议，研究肯尼亚高危儿童。最后， Loworn博士研究的持续成功吸引了两位博士后研究员（T32 获奖者）希望研究调节威尔姆斯肿瘤发生的机制，进一步证明他已经做好了准备 为了科学独立。目前的ROO提案总结了Loworn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确保R 01资金的时间轴。