RET/PTC Mediated Thyroid Tumorigenesis and NIS Modulation

RET/PTC 介导的甲状腺肿瘤发生和 NIS 调节

• 批准号: 7316496
• 负责人: Sissy M Jhiang
• 金额: $ 28.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-16 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316496
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; Age; Animal Model; Animals; Biological Markers; Cell surface; Cells; Childhood; Complex; Dimethyl Sulfoxide; Disease regression; Doxycycline; Goals; Human; Image; Iodine; LY294002; Life; Luciferases; Maintenance; Mediating; Monitor; Mus; Oncogenes; PD-98059; Papillary thyroid carcinoma; Pathogenesis; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Proteomics; RET/H4 Oncogene; Radiation; Radioisotopes; Research Personnel; Role; Signal Transduction; Sirolimus; Site-Directed Mutagenesis; Staging; Tetracycline; Tetracyclines; Thyroid Gland; Time; Tissue Microarray; Transgenic Mice; Translating; human SLC5A5 protein; in vivo; inhibitor/antagonist; older patient; pre-clinical; programs; proto-oncogene protein c-ret; research study; sodium-iodide symporter; symporter; thyroid neoplasm; transgene expression; tumor; tumor initiation; tumorigenesis; uptake

DESCRIPTION (provided by applicant): The RET/PTC oncogene, a rearranged form of the RET receptor tyrosine kinase, is believed to play an important role in the pathogenesis of papillary thyroid cancer (PTC), in particular in pediatric patients and those with prior radiation exposure. The long-term goal of the proposed project is to understand the underlying mechanisms of the effects of RET/PTC oncogene on tumorigenesis, progression, and radioiodine therapy 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 of RET/PTC1 in tumor maintenance/ progression. We are generating doxycycline-inducible thyroid-targeted RET/PTC 1-luciferase bi-transgenic mice; such that RET/PTC1 expression can be modulated by administration of doxycycline and thyroid tumor formation can be non-invasively monitored by MS¿1/2 imaging. We hypothesize that RET/PTC mediated tumor formation is modulated by the intrinsic proliferation capacity of thyrocytes at the time of RET/PTC activation. In Aim 2, we will delineate the underlying mechanisms of NIS modulation by phosphorylation and protein complex formation. We have identified four in vivo phosphorylation sites in NIS and have demonstrated possible significance of these four phosphorylation sites in modulating NIS activity. We will further characterize the functional significance of these four phosphorylation sites and identify signaling/kinases that modulate these phosphorylation sites. In addition, we will examine whether differences in NIS phosphorylation and NIS protein complexes contribute to the discordance between NIS cell surface levels and NIS activity. In Aim 3, we will screen for agents that selectively increase radioiodine accumulation in thyroid tumors using a pre-clinical animal model and examine RET/PTC1 effects on radionuclide uptake and retention in the thyroid of live animals.

描述（由申请人提供）：RET/PTC 癌基因是 RET 受体酪氨酸激酶的重排形式，被认为在甲状腺乳头状癌 (PTC) 的发病机制中发挥着重要作用，特别是在儿科患者和既往患有甲状腺乳头状癌的患者中。该项目的长期目标是了解 RET/PTC 癌基因对人类 PTC 肿瘤发生、进展和放射性碘治疗影响的潜在机制。在该提案中，确定了三个具体目标，在目标 1 中，我们将研究 RET/PTC1 在甲状腺肿瘤发生中的发生以及 RET/PTC1 在肿瘤维持/进展中的需求。 PTC 1-荧光素酶双转基因小鼠；通过施用多西环素可以调节 RET/PTC1 表达，并且可以非侵入性地形成甲状腺肿瘤由 MS 监控1/2 成像。我们追求 RET/PTC 介导的肿瘤形成是由 RET/PTC 激活时甲状腺细胞的内在增殖能力调节的。在目标 2 中，我们将描述通过磷酸化和蛋白质复合物调节 NIS 的潜在机制。我们已经鉴定了 NIS 中的四个体内磷酸化位点，并证明了这四个磷酸化位点在调节 NIS 活性中的可能重要性。我们将进一步表征这四个位点的功能意义。此外，我们将检查 NIS 磷酸化和 NIS 蛋白复合物的差异是否导致 NIS 细胞表面水平和 NIS 活性之间的不一致。在目标 3 中，我们将筛选试剂。使用临床前动物模型选择性增加甲状腺肿瘤中放射性碘的积累，并检查 RET/PTC1 对活体动物甲状腺中放射性核素摄取和保留的影响。