Vitamin D Control of TGFa/EFG Receptor Growth Signaling

描述（由申请人提供）：甲状旁腺激素（PTH）水平升高导致纤维性骨炎、骨质流失和心血管并发症，所有这些都显著增加了肾衰竭的发病率和死亡率。促甲状旁腺激素生成细胞增生是血清促甲状旁腺激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缺乏可促进肾衰竭患者甲状旁腺（PT）增生，但其潜在机制尚不清楚。我们对饲喂高磷饲料的尿毒症大鼠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（一种高度特异性的EGFR-酪氨酸激酶抑制剂（TKI））抑制EGFR激活，可使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说，即维生素D对PT增生的有效抑制可能是由于tgf /EGFR生长信号的下调。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细胞生长。在体外，维生素D通过拮抗EGFR- ERKI/2激活和cyclin D1反激活来抑制EGFR过度表达驱动的生长，并增强最大抑制剂量AG1478诱导的生长停滞。后者显示抗增殖维生素D的作用是不依赖于egfr的。本提案的总体目标是表征维生素D和TGFa/EGFR之间的拮抗相互作用及其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)激活自分泌TGFa/ egfr生长环对早期和晚期肾衰竭甲状旁腺增生和维生素D抵抗的实际贡献。2)维生素d抑制甲状旁腺增生的egfr依赖和独立机制。3)维生素d介导EGFR过表达细胞中EGFR生长信号抑制的分子机制。4)维生素d增强tki抑制EGFR过表达细胞生长的机制。通过确定致病机制，这些研究应该有助于设计更有效的治疗继发性甲状旁腺功能亢进的方法。

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.