Vitamin D Control of TGFa/EFG Receptor Growth Signaling

维生素 D 对 TGFa/EFG 受体生长信号的控制

• 批准号: 6892386
• 负责人: ADRIANA Silvia DUSSO
• 金额: $ 21.23万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892386
• 关键词: biological signal transduction; cell growth regulation; combination chemotherapy; drug resistance; endocrine disorder chemotherapy; endocrine pharmacology; endocrinology; epidermal growth factor; growth factor receptors; inhibitor /antagonist; intermolecular interaction; kinase inhibitor; laboratory rat; molecular pathology; parathyroid hormones; parathyroid hyperplasia; pathologic process; protein tyrosine kinase; renal failure; transforming growth factors; uremias; vitamin D; vitamin receptor

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.

描述（由申请人提供）：甲状旁腺激素（PTH）水平升高会导致骨炎，骨质流失和心血管并发症，所有这些都对肾衰竭中的发病率和死亡率的提高产生了显着贡献。产生PTH的细胞的增生是高血清PTH水平的主要原因。虽然众所周知，低钙血症，高磷酸血症和维生素D缺乏症会促进肾衰竭中的甲状旁腺（PT）增生，但潜在的机制知之甚少。我们对喂养高P饮食的尿毒症大鼠PT生长的研究表明，TGFA/EGFR途径的激活是PT增生的主要因素。高度特异性的EGFR-酪氨酸激酶抑制剂（TKI）抑制EGFR激活EGFR激活，可将尿emia-和高P诱导的PT增生减少60％。这一发现提出了这样一个假设，即维生素D对PT增生的有效抑制可能是由于TGFA/EGFR生长信号的下调而引起的。实际上，维生素D通过防止TGFA和EGFR的增加来抑制尿emia和高P诱导的PT细胞生长。在体外，维生素D通过拮抗EGFR激活ERKI/2和细胞周期蛋白D1的反式激活来阻止EGFR过表达驱动的生长，并增强最大抑制剂量AG1478引起的生长停滞。后者表现出与EGFR无关的抗增生性维生素D作用。该建议的总体目标是表征维生素D与TGFA/EGFR之间的拮抗相互作用及其在甲状旁腺增生的发病机理和治疗中的相关性。为此，我们建议使用TKI，1,25D和联合疗法来识别：1）在早期和晚期肾衰竭中，自分泌TGFA/EGFR-GROWTH环路对甲状旁腺增生和维生素D耐药性的实际贡献。 2）介导甲状旁腺增生的维生素D-抑制的EGFR依赖性和独立机制。 3）介导EGFR过表达细胞中EGFR增长信号的维生素D抑制维生素D抑制的分子机制。 4）介导TKI抑制EGFR过表达细胞的TKI抑制维生素D-抑制的机制。通过鉴定病原机制，这些研究应有助于设计更有效的次级甲状旁腺功能亢进症。