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

7.项目摘要/摘要 电子烟迅速流行起来，并在青少年中扩大了基础，因为他们的 比传统香烟更安全。流行病学估计表明电子烟蒸气(ECV) 在年轻人中有患哮喘的风险，而现在评估慢性阻塞性疾病的风险可能还为时过早 肺部疾病(COPD)。传统的香烟烟雾(CS)对COPD有很大的促进作用，并抑制 宿主防御增加了对感染的敏感性。啮齿动物模型显示由于ECV引起的易感性相似。 相对于成人，儿童和青少年对CS和ECV的反应仍然知之甚少。 呼吸道上皮形成一种结构性屏障，但也会分泌大量蛋白质进入保护肺的呼吸道。 形成天然粘膜防御系统的一部分。人的先天性粘膜防御系统 肺受到CS和ECV的影响，然而这些防御系统的失调如何导致肺部疾病并不是 安全。目前也不清楚接触时的年龄是否独立地导致了疾病。最重要的是 该项目的假设是ECV通过以下方式调节呼吸道上皮对环境刺激的反应 对天然粘膜防御蛋白的影响。我们将通过以下三个具体目标来解决该假设 我们还会将ECV与更广泛研究的CS进行比较。在目标1中，我们将确定ECV的效果 在婴儿、青少年和成年非人类灵长类动物的呼吸道上皮细胞中。我们会评估这些措施的影响 暴露在固有的粘膜防御系统上，以及对上皮细胞炎症的调节。在《目标2》中，我们 将研究改变表达最丰富的天然粘膜之一的水平和功能的影响 防御蛋白，SPLunc1。我们将用替代微生物的分子刺激呼吸道上皮细胞 感染并检测不同水平和功能活性对上皮细胞反应的调节 SPLunc1.在目标3中，我们将比较CS和ECV在小鼠模型中的作用。在此模式下，我们将 改变SPLunc1的水平，以确定其在这些暴露期间和随后调节炎症的能力 针对细菌感染的替代分子的挑战。我们将进一步确定SPLunc1函数是否可以 在CS和ECV暴露后，通过直接给药到肺部进行抢救。SPLunc1是一个很有前途的 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，寻求(1)获得机械，假说--的知识和实践经验。 通过有针对性的体外方法和啮齿动物模型推动研究和(2)接受指导培训 科学写作、研究计划管理和资质导致成功申请R01- 水平研究经费。SERCA K01将提供受保护的时间来实现这些目标和手段 为启动罗耶博士独立的生物医学研究生涯，为未来的拨款获得初步数据。

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.