Age-Dependent Effects of E-cigarette Vaping on Host Pathogen Defense

7.项目概要/摘要 电子烟迅速普及，由于其独特的功能，在青少年中的基础越来越广。 比传统香烟更安全。流行病学估计表明电子烟蒸汽（ECV） 在年轻人中有患哮喘的风险，而估计慢性阻塞性肺疾病的风险可能还为时过早。 肺疾病（COPD）。传统的香烟烟雾（CS）对COPD有很大的影响， 宿主防御增加了对感染的易感性。啮齿类动物模型表明对ECV的敏感性相似。 相对于成人，儿童和青少年对CS和ECV的反应如何仍然知之甚少。 气道上皮细胞形成结构屏障，但也分泌许多蛋白质进入气道，保护肺 并形成先天粘膜防御的一部分。先天性粘膜防御系统 肺受到CS和ECV的影响，然而这些防御机制的失调如何导致肺部疾病还不清楚。 清楚目前还不清楚暴露时的年龄是否独立地导致疾病。总体 该项目的假设是ECV通过以下途径调节气道上皮对环境刺激的反应： 对先天性粘膜防御蛋白的影响。我们将通过三个具体目标来解决这个假设， 我们还将比较ECV与更广泛研究的CS。在目标1中，我们将确定ECV的影响 在来自婴儿、青少年和成年非人灵长类动物的气道上皮细胞中。我们将评估 暴露于固有粘膜防御以及调节上皮细胞中的炎症。在目标2中， 将研究一种表达最丰富的先天性粘膜细胞的水平和功能的变化所产生的影响， 防御蛋白SPLUNC 1。我们将刺激呼吸道上皮细胞的分子， 感染，并检查不同水平和功能活性的上皮细胞的反应的调节， SPLUNC 1.在目标3中，我们将比较CS和ECV在小鼠模型中的作用。在这个模型中，我们将 改变SPLUNC 1的水平，以确定其在这些暴露期间和之后调节炎症的能力。 细菌感染的替代分子的挑战。我们将进一步确定SPLUNC 1函数是否可以 在CS和ECV暴露后，通过直接给药至肺部进行抢救。SPLUNC 1是一个很有前途的 候选人作为一种新的治疗方法，这些实验将有助于确定其疗效。候选人， 克里斯托弗·罗耶，DVM，博士，旨在（1）获得知识和实践经验的机械，假设- 通过相关的体外方法和啮齿动物模型推动研究;（2）接受以下方面的指导培训 科学写作，研究项目管理，以及成功申请R 01的granitarian- 研究经费水平。SERCA K 01将提供受保护的时间来实现这些目标和手段 以确保初步数据，为未来的赠款启动博士罗耶的独立生物医学研究生涯。

7. Project Summary/Abstract Electronic cigarettes have rapidly gained popularity and have a widened base among adolescents due to their perceived safety over traditional cigarettes. Epidemiological estimates indicate electronic cigarette vapor (ECV) carries a risk for asthma in young people whereas it may be too early to estimate risk for chronic obstructive pulmonary disease (COPD). Traditional cigarette smoke (CS) contributes strongly to COPD and suppresses host defenses increasing susceptibility to infection. Rodent models indicate similar susceptibility due to ECV. How children and adolescents respond to both CS and ECV, relative to adults, remains poorly understood. Airway epithelia form a structural barrier but also secrete numerous proteins into the airway that protect the lung from the environment and form part of the innate mucosal defense. The innate mucosal defense system of the lung is affected by CS and ECV however how dysregulation of these defenses contributes to lung disease is not clear. It is also unclear whether the age at exposure independently contributes to disease. The overarching hypothesis for this project is that ECV modulates the airway epithelial response to environmental stimuli through the effects on innate mucosal defense proteins. We will address the hypothesis through three specific aims in which we will also compare ECV to the more widely studied CS. In Aim 1 we will determine the effects of ECV in airway epithelial cells from infant, adolescent, and adult nonhuman primates. We will assess the effects of the exposures on the innate mucosal defenses as well as the regulation of inflammation in the epithelia. In Aim 2 we will examine the effects of changing levels and function of one of the most abundantly expressed innate mucosal defense proteins, SPLUNC1. We will stimulate airway epithelia with molecules that are surrogates for microbial infection and examine the regulation of the response of epithelia by different levels and functional activity of SPLUNC1. In Aim 3 we will compare the effects of CS and ECV in a mouse model. Within this model we will vary the levels of SPLUNC1 to determine its ability to regulate inflammation during these exposures and following a challenge with a surrogate molecule for bacterial infection. We will further determine if SPLUNC1 function can be rescued following CS and ECV exposure by administration directly to the lungs. SPLUNC1 is a promising candidate as a new class of therapeutics and these experiments will help determine its efficacy. The candidate, Christopher Royer, DVM, PhD, seeks to (1) gain knowledge and practical experience in mechanistic, hypothesis- driven research through pertinent in vitro methods and rodent models and (2) receive mentored training in scientific writing, research program management, and grantsmanship leading to successful application for R01- level research funding. The SERCA K01 will provide protected time to achieve these objectives and the means to secure preliminary data for future grants launching Dr. Royer's independent biomedical research career.