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. |