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.

Public Health Relevance

Successful transition from the mentored to the independent phases of this Pathway to Independence Award is relevant not only for completing this important study of mechanisms at play in failed terminal differentiation and organ maturation that facilitate embryonal tumorigenesis, but also for Dr. Loworn to secure funding as an independent investigator so that he can continue to make significant contributions to this burgeoning field at the Interface between developmental and cancer biology.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
5R00CA135695-05
Application #
8309471
Study Section
Special Emphasis Panel (NSS)
Program Officer
Spalholz, Barbara A
Project Start
2008-09-15
Project End
2014-02-28
Budget Start
2012-09-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$241,529
Indirect Cost
$86,702
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Murphy, Andrew J; Pierce, Janene; de Caestecker, Christian et al. (2014) CITED1 confers stemness to Wilms tumor and enhances tumorigenic responses when enriched in the nucleus. Oncotarget 5:386-402
Murphy, Andrew J; Pierce, Janene; de Caestecker, Christian et al. (2014) Aberrant activation, nuclear localization, and phosphorylation of Yes-associated protein-1 in the embryonic kidney and Wilms tumor. Pediatr Blood Cancer 61:198-205
Murphy, Andrew J; Ayers, Gregory D; Hilmes, Melissa A et al. (2013) Imaging analysis of hepatoblastoma resectability across neoadjuvant chemotherapy. J Pediatr Surg 48:1239-48
Rauth, Thomas P; Slone, Jeremy; Crane, Gabriella et al. (2011) Laparoscopic nephron-sparing resection of synchronous Wilms tumors in a case of hyperplastic perilobar nephroblastomatosis. J Pediatr Surg 46:983-8
Axt, Jason; Murphy, Andrew J; Seeley, Erin H et al. (2011) Race disparities in Wilms tumor incidence and biology. J Surg Res 170:112-9