Network-based analysis of disease-associated epigenetic changes in youth electronic cigarette users

在美国，年轻人广泛使用电子烟（e-cigs）是一个重大的公共卫生问题， 世界上许多地方。到目前为止，电子烟对这一弱势群体的长期健康影响主要是 未知电子烟烟雾中存在的许多有毒物质和致癌物质通过表观遗传作用发挥其生物学效应 可能导致疾病相关基因失调的变化。长链非编码RNA（lncRNA）是关键 健康和疾病状态下基因表达的表观遗传调节因子。 方法：研究lncRNA介导的基因调控及其与疾病发展的关系， 我们将对年轻电子烟用户的细胞和组织进行RNA-seq和基于网络的分析 与非用户相比。目标1a：使用系统生物学方法，我们将检测异常lncRNA， 他们的互动网络，驱动基因失调，在青年电子烟用户。检测到的lncRNAs控制着 青少年电子烟使用者的基因失调可以作为电子烟暴露和影响的新生物标志物。目的 1b：应用先进的预测方法，我们将确定哪些疾病与异常相关。 在年轻的电子烟用户中检测到lncRNAs。青少年电子烟使用者中与特定 疾病可以用于vaping的风险评估。目标2：使用计算建模，我们将找到 异常lncRNA与吸电子烟的强度和持续时间之间的关联（即，剂量）和 年轻人使用的vaping产品的特点。确定影响lncRNA的产品特征- 青少年电子烟使用者介导的基因失调可以告知FDA对烟草产品的监管，以保护 青年和促进公共卫生。 对RFA-OD-21-004的响应：本提案将最大限度地利用我们的现有生物标本 最近完成的NIDCR资助的项目，其研究对象是通过与南加州大学合作招募的- TCORS由FDA赞助，|CTP。这是一个独特的生物标本的集合， 南加州的人口样本。在美国没有公开的储存库提供类似的标本 这一提议所需的。我们将为青少年使用电子烟的健康风险提供科学证据， 告知FDA对烟草产品的监管，以保护这一弱势群体并促进公众健康。 健康我们将采用创新的方法来解决本RFA中的两个科学兴趣领域，包括 评估（1）暴露;（2）年轻人吸电子烟的潜在危害，他们是一个特殊的人群， 本案无关通过阐明年轻人使用电子烟的生物学后果背后的分子变化， 我们将开发新的暴露和影响的生物标志物。这些生物标志物将具有显著的实用性， 评估这一弱势群体使用电子烟的健康风险。通过确定电子烟剂量和产品 特性可以调节青少年电子烟使用者的诱导生物效应，我们将提供迫切需要的 这些数据为FDA对烟草产品的监管提供了信息，以保护青少年和促进公众健康。

The widespread use of electronic cigarettes (e-cigs) by youth is a significant public health problem in the US and many parts of the world. To date, the long-term health effects of e-cig use in this vulnerable population are largely unknown. Many toxicants and carcinogens present in e-cig vapor exert their biological effects through epigenetic changes that can cause dysregulation of disease-related genes. Long non-coding RNAs (lncRNAs) are key epigenetic regulators of gene expression in health and disease states. Approach: To investigate lncRNA-mediated gene regulation and its association with disease development in youth vapers, we will perform RNA-seq and network-based analyses on cells and tissues of youth e-cig users as compared to non-users. Aim 1a: Using a systems biology approach, we will detect aberrant lncRNAs and their interaction networks that drive gene dysregulation in youth e-cig users. The detected lncRNAs that govern gene dysregulation in youth e-cig users can serve as novel biomarkers of exposure and effects for vaping. Aim 1b: Applying advanced prediction methods, we will identify which diseases are associated with the aberrant lncRNAs detected in youth e-cig users. Aberrant lncRNAs in youth e-cig users that are associated with specific diseases can be used for risk assessment of vaping. Aim 2: Using computational modeling, we will find the associations between aberrant lncRNAs and the intensity and duration of vaping (i.e., dose) and the characteristics of vaping products used by youth. Identifying product characteristics that influence the lncRNA- mediated gene dysregulation in youth e-cig users can inform the FDA’s regulation of tobacco products to protect youth and promote public health. Responsiveness to RFA-OD-21-004: This proposal will maximize the use of existing biospecimens from our recently completed NIDCR-funded project whose study subjects were recruited through collaboration with USC- TCORS, which is sponsored by the FDA|CTP. This is a unique collection of biospecimens from a representative sample of population in Southern California. No publicly available repository in the US offers similar specimens needed for this proposal. We will generate scientific evidence on the health risks of e-cig use in youth, thus informing the FDA’s regulation of tobacco products to protect this vulnerable population and promote public health. We will use an innovative approach to address two scientific interest areas in this RFA, including assessment of (1) exposure; and (2) potential harm from vaping in youth, who are a population of special relevance. By elucidating the molecular changes that underlie the biological consequences of e-cig use in youth, we will develop novel biomarkers of exposure and effects. These biomarkers will have significant utility for assessing the health risks of e-cig use in this vulnerable population. By determining how vaping dose and product characteristics can modulate the induced biological effects in youth e-cig users, we will provide urgently needed data to inform the FDA’s regulation of tobacco products to protect youth and promote public health.