Role of Vitamin D Metabolism in CRS

维生素 D 代谢在 CRS 中的作用

• 批准号: 10408804
• 负责人: Jennifer Konopa Mulligan
• 金额: $ 48.51万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408804
• 关键词: Affect; Allergic rhinitis; Anti-Inflammatory Agents; Antigens; Aspergillus fumigatus; Asthma; Automobile Driving; CYP27B1 gene; Cell physiology; Cell secretion; Cholecalciferol; Chronic; Chronic Obstructive Pulmonary Disease; Chronic Sinusitis; Data; Diet; Disease; Enzymes; Epithelial; Epithelial Cells; FGF2 gene; Fibroblasts; Heart failure; Human; Hydroxylation; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Investigation; Life Style; Mediator of activation protein; Metabolism; Mixed Function Oxygenases; Mus; Nasal Polyps; Nutrient; Outcome Study; Patients; Permeability; Phenotype; Population; Production; Property; Quality of life; Regulation; Respiratory Disease; Respiratory physiology; Role; Severity of illness; Source; Steroids; Symptoms; System; Testing; United States; Vitamin D; airway epithelium; airway inflammation; base; cell type; chemokine; chronic rhinosinusitis; cytokine; efficacy testing; feasibility testing; improved; in vivo; insight; mouse model; novel; prevent; vitamin metabolism

Chronic rhinosinusitis (CRS) affects 16% of the United States' population with few proven treatments. CRS with nasal polyps (CRSwNP) is the most difficult form of the disease to treat and has a negative impact on quality of life that exceeds other chronic conditions, such as heart failure and chronic obstructive pulmonary disease. CRSwNP is characterized by a type 2 skewed inflammatory profile and increased numbers of sinonasal fibroblasts. Given its anti-inflammatory properties, vitamin D3 (VD3) may serve as a potential novel treatment for CRSwNP. We have shown that patients with CRSwNP have alterations to the vitamin D system that extends beyond a simple nutrient deficiency caused by diet or lifestyle. CRSwNP patients have reduced sinonasal levels of the active metabolite of VD3, 1,25(OH)2D3, despite adequate circulating forms of its precursors or 1,25(OH)2D3 itself. Furthermore, reductions in human sinonasal epithelial cell (HSNEC) levels of 1α-hydroxylase, the enzyme responsible for the final hydroxylation to make 1,25(OH)2D3, is associated with more severe CRSwNP. The scientific premise of these studies is to determine if increasing local levels of 1,25(OH)2D3 can reduce sinonasal inflammation and serve as a potential treatment for CRSwNP. In preliminary studies, we observed that 1,25(OH)2D3 reduced human sinonasal epithelial cell (HSNEC) and sinonasal fibroblast (HSNF) production of type 2 mediators. While HSNF can respond to 1,25(OH)2D3, they are not capable of metabolizing it themselves, leaving them dependent on other cell types, mainly HSNECs, as a source of 1,25(OH)2D3. Based on these and other data, we hypothesize that impaired 25(OH)D3 metabolism by HSNECs results in local deficiencies in 1,25(OH)2D3, thereby driving the type 2 inflammation and fibroblast activation associated with CRSwNP. We will test this hypothesis through the execution of the following aims. Aim 1 will examine the contribution of 25(OH)D3 metabolism to HSNEC-derived inflammation and determine the ability of 1,25(OH)2D3 to modulate endogenous and exogenously-stimulated inflammation by control and CRSwNP HSNECs. In Aim 2 we will determine the role of human sinonasal epithelial 25(OH)D3 metabolism and 1,25(OH)2D3 in the regulation of fibroblast-derived inflammation. In Aim 3 we will test, in vivo, how alterations in sinonasal vitamin D metabolism regulates inflammation and disease severity utilizing a murine model of atopic CRS. With respect to outcomes, these studies will greatly expand our understanding of how local 25(OH)D3 metabolism regulates sinonasal inflammation and will test the feasibility and potential efficacy of sinonasal delivery of 1,25(OH)2D3 as a treatment for CRSwNP. In addition to the direct applicability of these findings to CRSwNP, our results may be relevant to other respiratory diseases, most notably to asthma and allergic rhinitis.

慢性鼻塞炎（CRS）影响了美国人口的16％，几乎没有经过证实的治疗方法。 患有鼻息肉（CRSWNP）的CR是治疗疾病中最困难的形式，并产生负面影响 关于超过其他慢性疾病的生活质量，例如心力衰竭和慢性阻塞性肺 疾病。 CRSWNP的特征是2型偏斜的炎症概况和增加的数量 鼻窦成纤维细胞。鉴于其抗炎特性，维生素D3（VD3）可能是潜在的新型 CRSWNP的治疗。我们已经表明，CRSWNP患者对维生素D系统有所改变 这超出了饮食或生活方式引起的简单营养不足。 CRSWNP患者减少了 VD3的活性代谢物的鼻窦水平，1,25（OH）2d3，dospite足够的循环形式 前体或1,25（OH）2d3本身。此外，人鼻鼻上皮细胞（HSNEC）水平的降低 在1α-羟化酶中，负责最终羟基化的酶使1,25（OH）2d3与 更严重的CRSWNP。这些研究的科学前提是确定是否增加了本地水平 1,25（OH）2d3可以减少鼻纳纳纳斯注射，并作为CRSWNP的潜在治疗方法。在 初步研究，我们观察到1,25（OH）2d3降低了人类鼻鼻上皮细胞（HSNEC）和 鼻窦成纤维细胞（HSNF）生产2型介体。虽然HSNF可以回应1,25（OH）2d3，但 无法自己代谢，使它们取决于其他细胞类型，主要是HSNEC， 作为1,25（OH）2d3的来源。 基于这些数据和其他数据，我们假设HSNEC损害了25（OH）D3代谢 结果在1,25（OH）2d3中导致局部缺陷，从而驱动2型注射和成纤维细胞激活 与CRSWNP相关。我们将通过执行以下目的来检验这一假设。目标1 将检查25（OH）D3代谢对HSNEC衍生注射的贡献，并确定 1,25（OH）2d3的能力通过对照和对照和外源刺激的注射和外源刺激的能力 CRSWNP HSNEC。在AIM 2中，我们将确定人类鼻鼻上皮25（OH）D3代谢的作用 在成纤维细胞衍生的炎症的调节中，有1,25（OH）2d3。在AIM 3中，我们将在体内测试如何 Sinonasal维生素D代谢的改变可以通过鼠调节感染和疾病严重程度 特应当CRS的模型。关于结果，这些研究将大大扩展我们对 局部25（OH）D3代谢调节鼻窦感染，并将测试可行性和潜在效率 1,25（OH）2d3作为CRSWNP的治疗方法。除了直接适用 这些对CRSWNP的发现，我们的结果可能与其他呼吸道疾病有关，最著名的是哮喘 和过敏性鼻炎。