Vitamin D Control of TGFa/EFG Receptor Growth Signaling

描述(由申请人提供)：甲状旁腺激素(PTH)水平升高会导致纤维性骨炎、骨丢失和心血管并发症，所有这些都会显著增加肾功能衰竭的发病率和死亡率。甲状旁腺激素产生细胞的增殖是血清甲状旁腺素水平升高的主要原因。虽然已知低钙血症、高磷血症和维生素D缺乏促进肾功能衰竭时甲状旁腺(PT)的增殖，但其潜在的机制尚不清楚。我们对高磷饲料喂养的尿毒症大鼠PT生长的研究表明，TGFa/EGFR通路的激活是PT增生的主要原因。AG1478是一种高度特异的EGFR酪氨酸激酶抑制剂(TKI)，通过抑制EGFR的激活，可以将尿毒症和高磷诱导的PT增生减少60%。这一发现提出了一种假设，即维生素D对甲状旁腺增生的有效抑制可能是由于下调了TGFa/EGFR生长信号。事实上，维生素D通过阻止TGFa和EGFR的增加来抑制尿毒症和高磷诱导的PT细胞的生长。在体外，维生素D通过拮抗ERKI/2的EGFR激活和细胞周期蛋白D1的反式激活来抑制EGFR过表达所致的生长抑制，并增强最大抑制剂量AG1478所诱导的生长抑制。后者显示了不依赖于EGFR的抗增殖维生素D作用。该建议的总体目标是表征维生素D和TGFa/EGFR之间的拮抗相互作用，以及它们在甲状旁腺增生的发病机制和治疗中的相关性。为此，我们建议使用TKI、1，25D和联合治疗来确定：1)在早期和晚期肾功能衰竭中，自分泌TGFa/EGFR生长环激活对甲状旁腺增生和维生素D抵抗的实际贡献。2)EGFR依赖和独立的介导维生素D抑制甲状旁腺增生的机制。3)维生素D抑制EGFR过表达细胞生长信号的分子机制。4)维生素D增强TKI的机制--抑制EGFR过表达细胞的生长。通过确定致病机制，这些研究应该有助于设计更有效的继发性甲状旁腺功能亢进的治疗方法。

DESCRIPTION (provided by applicant): Elevated parathyroid hormone (PTH) levels cause osteitis fibrosa, bone loss and cardiovascular complications, all of which contribute significantly to increased morbidity and mortality in renal failure. Hyperplasia of PTH-producing cells is a major cause of high serum PTH levels. While it is known that hypocalcemia, hyperphosphatemia, and vitamin D deficiency promote parathyroid (PT) hyperplasia in renal failure, the underlying mechanisms are poorly understood. Our studies of PT growth in uremic rats fed a high P diet have shown that activation of the TGFa/EGFR pathway is a major contributor to PT hyperplasia. Inhibition of EGFR activation by AG1478, a highly specific EGFR-tyrosine kinase inhibitor (TKI), reduces uremia- and high P-induced PT hyperplasia by 60%. This finding raises the hypothesis that the potent inhibition of PT hyperplasia by vitamin D could result from downregulation of TGFa/EGFR growth signals. In fact, vitamin D suppresses the PT cell growth induced by uremia and high P by preventing increases in TGFa and EGFR. In vitro, vitamin D arrests the growth driven by EGFR overexpression by antagonizing EGFR-activation of ERKI/2 and transactivation of cyclin D1, and potentiates the growth arrest induced by maximally inhibitory doses of AG1478. The latter demonstrates antiproliferative vitamin D actions that are EGFR-independent. The overall goal of this proposal is to characterize the antagonistic interactions between vitamin D and TGFa/EGFR and their relevance in the pathogenesis and treatment of parathyroid hyperplasia. To this end, we propose to use TKI, 1,25D and combined therapy to identify: 1) Actual contribution of activation of the autocrine TGFa/EGFR-growth loop to parathyroid hyperplasia and vitamin D resistance in early and advanced renal failure. 2) EGFR-dependent and independent mechanisms mediating vitamin D-suppression of parathyroid hyperplasia. 3) Molecular mechanisms mediating vitamin D-inhibition of EGFR-growth signals in EGFR overexpressing cells. 4) Mechanisms mediating vitamin D-potentiation of TKI-inhibition of growth in EGFR overexpressing cells. By identifying pathogenic mechanisms, these studies should help design more effective therapies for secondary hyperparathyroidism.