The RET/PTC oncogene, a rearranged form of the RET receptor tyrosine kinase, is believed to play animportant role in the pathogenesis of papillary thyroid cancer (PTC), in particular in pediatric patients andthose with prior radiation exposure. The long-term goal of the proposed project is to understand theunderlying mechanisms of the effects of RET/PTC oncogene on tumorigenesis, progression, and radioiodinetherapy of human PTC. In this proposal, three specific aims are identified.
In Aim 1, we will investigate the onset of RET/PTC1 in thyroid tumorigenesis and the requirement ofRET/PTC1 in tumor maintenance/ progression. We are generating doxycycline-inducible thyroid-targetedRET/PTC1-luciferase bi-transgenic mice; such that RET/PTC1 expression can be modulated byadministration of doxycycline and thyroid tumor formation can be non-invasively monitored by MS imaging. We hypothesize that RET/PTC mediated tumor formation is modulated by the intrinsic proliferationcapacity of thyrocytes at the time of RET/PTC activation.
In Aim 2, we will delineate the underlying mechanisms of NIS modulation by phosphorylation and proteincomplex formation. We have identified four in vivo phosphorylation sites in NIS and have demonstratedpossible significance of these four phosphorylation sites in modulating NIS activity. We will furthercharacterize the functional significance of these four phosphorylation sites and identify signaling/kinases thatmodulate these phosphorylation sites. In addition, we will examine whether differences in NISphosphorylation and NIS protein complexes contributes to the discordance between NIS cell surface levelsand NIS activity.
In Aim 3, we will screen for agents that selectively increase radioiodine accumulation in thyroid tumors usinga pre-clinical animal model and examine RET/PTC1 effects on radionuclide uptake and retention in thethyroid of live animals.
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