Cathelicidin and Vitamin D: Impact on Populations At-Risk and with COPD

 描述（由申请人提供）：了解导致肺功能下降的机制（包括慢性阻塞性肺疾病（COPD）在内的阻塞性肺疾病的生理标志）对于提供改善肺部健康的干预措施是必要的。在本申请中，我们建议检查抗微生物肽凯萨林菌素及其主要调节剂维生素D在肺功能损害、呼吸道感染和COPD急性加重中的作用，以及评估口服维生素D补充对人类肺凯萨林菌素水平的影响。Cathelicidin在肺中具有杀菌和炎症活性，并受维生素D水平调节。我们的假设是，cathelicidin水平的降低与肺功能的加速下降有关，尽管这是一种部分由感染增加和COPD加重介导的途径。我们假设，在维生素D不足的患者中，cathelicidin对肺功能的影响更大，口服维生素D补充剂将提高肺室中的cathelicidin水平，从而恢复肺cathelicidin缺乏症。具体而言，通过对城市主要是非洲裔美国人的奥尔兹发展高风险人群进行的队列研究中的纵向调查，我们将描述380名参与者的肺功能下降率，随后进行长达6年的连续肺功能测定。将检查凯萨林菌素和维生素D的基线和重复测量值，作为肺功能下降和呼吸道感染的独立预测因素。另外，使用2100名入组COPD亚群和中间结局指标研究（SPIROMICS）的确诊COPD受试者的纵向数据，将检查血组织蛋白酶抑制素和维生素D的基线指标，作为3年内纵向FEV 1下降和COPD急性加重的独立预测因素。在这两个队列中，同时进行维生素D测量将允许评价前药和修饰剂对凯萨林菌素-肺结局关系的影响。最后，我们将测量40名维生素D不足的个体在口服维生素D补充剂8周前后的血液和肺灌洗液cathelicidin水平，以确定维生素D补充剂对cathelicidin水平的影响。这些目标的实现将有力地确定 cathelicidin在肺功能下降和不利的肺部结果在独特的人群中的风险和患病的个人。此外，本申请的目的直接或间接地致力于最终理解容易测量的血液标记物凯萨林菌素是否可以告知谁可以从维生素D补充剂中受益以预防慢性肺病。这项应用的结果将导致一项治疗干预研究，这将提供进一步的机会，以提高我们对维生素D，cathelicidin和肺功能之间关系的理解。

 DESCRIPTION (provided by applicant): Understanding mechanisms leading to decrements in lung function, the physiologic hallmark of obstructive lung diseases including chronic obstructive pulmonary disease (COPD), are necessary to inform interventions to improve lung health. In this application, we propose to examine the role of the antimicrobial peptide cathelicidin, and its primary regulator vitamin D, in lung function impairment, respiratory infections and acute exacerbations of COPD as well as evaluate the effect of oral vitamin D supplementation on lung cathelicidin levels in humans. Cathelicidin has bactericidal and inflammatory activities in the lung and is regulated by vitamin D levels. Our hypothesis is that reduced cathelicidin levels are associated with accelerated lung function decline though a pathway partially mediated by increased infections and COPD exacerbations. We hypothesize the effect of cathelicidin on lung function is greater in those with vitamin D insufficiency and that oral vitamin D supplementation will raise cathelicidin levels in the pulmonary compartment, thereby restoring lung cathelicidin deficiency. Specifically, through longitudinal investigation nested within an ongoing cohort study of urban, predominantly African-American individuals at high risk for development of OLDs, we will characterize the rate of lung function decline in 380 participants followed with serial spirometry measures for up to six years. Baseline and repeated measures of cathelicidin and vitamin D will be examined as independent predictors of lung function decline and respiratory infections. Separately, using longitudinal data from 2100 participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) study with established COPD, baseline measures of blood cathelicidin and vitamin D will be examined as an independent predictor of longitudinal FEV1 decline and COPD exacerbations over three years. In both cohorts, concurrent vitamin D measurements will permit evaluation of antecedent and modifier on the cathelicidin-lung outcomes relationships. Finally, we will measure blood and lung lavage cathelicidin levels in 40 vitamin D insufficient individuals before and after eight weeks of oral vitamin D supplementation to determine the effect of vitamin D supplementation on cathelicidin levels. Completion of these aims will provide a robust determination of the role of cathelicidin in lung function decline and adverse pulmonary outcomes in unique populations of at-risk and diseased individuals. Moreover, the aims of this application directly or indirectly wor towards ultimately understanding if a readily measurable blood marker, cathelicidin, can inform who may benefit from vitamin D supplementation to prevent chronic lung disease. The results from this application would lead to a therapeutic intervention study that will provide further opportunities to improve our understanding of the relationship between vitamin D, cathelicidin and lung function.