Vitamin D Status in Pulmonary Fibrosis

描述(由申请人提供)： 特发性肺纤维化是一种病因不明的弥漫性间质性肺疾病，以慢性炎症和进行性纤维化为特征，可导致3年内50%的死亡率。目前，IPF没有有效的治疗方法，因为它对目前可用的治疗方法反应很差，包括皮质类固醇和其他免疫抑制剂。因此，迫切需要开发能够延缓或逆转肺纤维化的药理药物。越来越多的证据表明，转化生长因子-β在肺纤维化的发病机制中起重要作用。拮抗剂可能是肺纤维化的重要治疗靶点。我们对抑制转化生长因子作用的途径的研究？这使得我们开始研究维生素D及其受体(VDR)的信号转导机制。在这个项目中，我们将检验这样一种假设，即肺是1，25二羟基维生素D的靶器官，肺中维生素D代谢和信号的失调与进行性IPF有关。这一建议的目的是：i)对IPF和对照组的肺和全身维生素D代谢物进行定量；ii)确定维生素D受体在肺中的特异性表达和激活状态；以及iii)表征维生素D25、11和24羟基酶在肺中的表达和分布。总而言之，这些研究将为维生素D信号通路调节肺内稳态提供重要的机械性见解。公共卫生相关性：在试图确定疾病机制的过程中，该项目的目标是建立维生素D缺乏与肺纤维化之间的联系。这项研究对治疗其他器官的疤痕疾病具有更广泛的意义。(摘要结束)

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis is a diffuse interstitial lung disease of unknown etiology characterized by chronic inflammation and progressive fibrosis and carries a 3-year, 50% mortality. Currently, there are no effective treatments for IPF as it responds poorly to currently available therapy, which consists of corticosteroids and other immunosuppressive agents. Hence, there is a critical need to develop pharmacologic agents that delay or reverse pulmonary fibrosis. Accumulating evidence indicates that transforming growth factor-beta plays an important role in the pathogenesis of pulmonary fibrosis, and therefore TGF? antagonists may serve as important therapeutic target for pulmonary fibrosis. Our search for pathways that inhibit the actions of TGF? led us to the study of signal transduction by Vitamin D and its receptor (VDR). In this project we will test the hypothesis that the lung is a target organ for 1,25 dihydroxyvitamin D and that dysregulated Vitamin D metabolism and signaling in lung is associated with progressive IPF. The aims of this proposal are to: i) quantitate lung and systemic Vitamin D metabolites in IPF and control subjects ii) determine lung-specific expression and activation state of the Vitamin D receptor, and iii) characterize the expression and distribution of the Vitamin D 25-, 11-, and 24- hydroxylases in the lung. Collectively, these studies will provide important mechanistic insights into the regulation of lung homeostasis by Vitamin D signaling pathways. PUBLIC HEALTH RELEVANCE: In trying to determine a mechanism of disease, the goal of this project is to establish a link between vitamin D deficiency and pulmonary fibrosis. This research has broader implications for the treatment of scarring diseases of other organs. (End of Abstract)