Vitamin D Status in Pulmonary Fibrosis

维生素 D 在肺纤维化中的地位

• 批准号: 7837625
• 负责人: ALLAN RAMIREZ
• 金额: $ 2.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-11 至 2010-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837625
• 关键词: 1,25 (OH) vitamin D; Adrenal Cortex Hormones; Area; Biocompatible Materials; Cells; Characteristics; Chronic; Cicatrix; Clinical; Connective Tissue; Deposition; Development; Diagnosis; Diffuse; Dihydroxycholecalciferols; Disease; Epithelial Cells; Etiology; Fibroblasts; Fibrosis; Goals; Hamman-Rich syndrome; Homeostasis; Hormones; Immunohistochemistry; Immunosuppressive Agents; Inflammation; Interstitial Lung Diseases; Investigation; Lesion; Link; Lung; Lung diseases; Mediating; Metabolism; Mixed Function Oxygenases; Modeling; Mus; Myofibroblast; Organ; Pathogenesis; Pathway interactions; Patients; Play; Prevalence; Process; Pulmonary Fibrosis; Receptor Activation; Regulation; Relative (related person); Reporting; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Structure of parenchyma of lung; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transforming Growth Factors; Transplantation; United States; Vitamin D; Vitamin D Deficiency; Vitamin D3 Receptor; Waiting Lists; abstracting; analog; base; cytokine; effective therapy; insight; mortality; novel; outcome forecast; public health relevance; receptor; stem; therapeutic target

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)

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病，其特征是慢性炎症和进行性纤维化，3年死亡率为50%。目前，IPF尚无有效的治疗方法，因为其对目前可用的治疗（包括皮质类固醇和其他免疫抑制剂）反应较差。因此，迫切需要开发延迟或逆转肺纤维化的药理学试剂。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着重要作用，因此TGF？拮抗剂可作为肺纤维化的重要治疗靶点。我们寻找抑制TGF作用的途径？导致我们研究维生素D及其受体（VDR）的信号转导。在本项目中，我们将检验肺是1，25二羟维生素D的靶器官以及肺中维生素D代谢和信号传导失调与进行性IPF相关的假设。本提案的目的是：i）定量IPF和对照受试者的肺和全身维生素D代谢物，ii）确定维生素D受体的肺特异性表达和活化状态，以及iii）表征肺中维生素D 25-、11-和24-羟化酶的表达和分布。总的来说，这些研究将为维生素D信号通路调节肺稳态提供重要的机制见解。 公共卫生相关性：在试图确定疾病的机制时，该项目的目标是建立维生素D缺乏和肺纤维化之间的联系。这项研究对其他器官瘢痕性疾病的治疗具有更广泛的意义。 (End摘要）