Developmental Nicotine Exposure & Transgenerationally Altered Lung Phenotype

发育期尼古丁暴露

• 批准号: 9027005
• 负责人: VIRENDER K REHAN
• 金额: $ 41.07万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9027005
• 关键词: Address; Adult; Affect; Agonist; Asthma; Cells; Childhood; Childhood Asthma; Chronic lung disease; Clinical; Data; Development; Elderly; Environmental Exposure; Epidemic; Epidemiology; Epigenetic Process; Exposure to; Female; Fetal Lung; Fibroblasts; Future Generations; Gender; Generations; Genetic; Genetic Variation; Germ Lines; Gonadal structure; Individual; Lead; Life; Lung; Lung diseases; Mediating; Mesenchymal Differentiation; Modeling; Molecular; National Heart, Lung, and Blood Institute; Nicotine; PPAR gamma; Parents; Pathogenesis; Pathway interactions; Perinatal; Perinatal Exposure; Phenotype; Predisposition; Pregnancy; Protein Isoforms; Public Health; Rattus; Risk; Risk Factors; Rodent Model; Signal Pathway; Signal Transduction; Smoke; Smooth Muscle Myocytes; Specificity; Thick; airway hyperresponsiveness; airway muscle; base; cigarette smoking; disorder risk; environmental tobacco smoke exposure; imprint; innovation; insight; lung development; male; maternal cigarette smoking; novel; offspring; prevent; programs; public health relevance; respiratory smooth muscle; response; rosiglitazone; sex; transmission process

 DESCRIPTION (provided by applicant): This application is in response to NHLBI TOSI HL-131: Exposure of the developing lung to cigarette smoke is an independent risk factor for the development of chronic lung disease (CLD), including asthma in later life. Even more importantly, recently, it has been shown that by altering specific developmental signaling pathways necessary for fetal lung development, the perinatal nicotine exposure-related CLD risk is not restricted only to the nicotine exposed offspring, but is also transmitted transgenerationally to the progeny of the subsequent non-exposed offspring (Rehan et al, AJP Lung; 2013;305:L501-7). Specifically, nicotine alters the normal differentiation of mesenchymal cells in the developing lung by stimulating the Wnt pathway, inhibiting PPARɣ signaling, resulting in the myogenic phenotype of the airway smooth muscle (ASM) cells. Interestingly, these effects are sex-specific, with the molecular and functional effects on ASM cells seen exclusively in males. Importantly, PPARɣ agonists, which are potent Wnt antagonists, can inhibit and/or reverse these effects. Hypothesizing that these effects are determined by nicotine-induced epigenetic changes in the gonadal germ line, which lead to lung specific molecular and functional effects, we propose to examine the mechanistic basis for the 1) transgenerational (TG) transmission, and 2) gender-specificity of perinatal nicotine exposure-induced offspring lung hyperresponsive phenotype. In Aim 1, we will determine whether the perinatal nicotine exposure-induced lung phenotype is transmitted via the male vs. female germline (Aim 1A), whether it is affected by the genetic diversity of parents (Aim 1B), and whether the lung phenotype seen in childhood is also seen in adulthood (Aim 1C). In Aim 2, we will determine whether the more pronounced perinatal nicotine exposure-induced pulmonary phenotype seen in males is determined by the differential PKC expression and activation in ASM cells of males vs. females (Aim 2A) and whether this is abrogated by blocking the specific PKC isoform involved (Aim 2B). In Aim 3, we will determine whether perinatal nicotine exposure-induced germ line and ASM epigenetic changes are transmitted from F1 to F3 generation (Aim 3A) and whether concomitant suppression of nicotine-induced Wnt activation, using PPARɣ agonist rosiglitazone, blocks these epigenetic changes and protects against perinatal nicotine-induced TG transmission of the lung myogenic phenotype (Aim 3B). The concepts put forward in this proposal are totally novel and innovative, thus advancing the field significantly by addressing the fundamental mechanism(s) that explain the detrimental effects of maternal smoking not only on the exposed offspring, but also on the many generations that follow. Using this comprehensive cell-molecular-epigenetic approach, the proposed studies are likely to not only generate new, pivotal molecular data that could significantly impact our understanding of the pathogenesis of CLD, but also provide novel mechanistic information underlying CLD risk, paving the way for studying molecular mechanisms underlying TG effects on a host of other environmental exposures.

 描述（通过应用程序提出）：此应用是响应NHLBI TOSI HL-131：发育中的肺暴露于卷烟和吊坠危险因素，用于开发慢性肺肺疾病（CLD），最近，它已被抛弃通过高高的发育信号通路，必要的胎儿肺肺肺活量与尼古丁相关的CLD风险并不限制随后未暴露的后代的后代（Rehan等人，AJP肺； 2013; 2013; 305：L501-7）。通过刺激Wnt途径，遗传了PPARɣ信号，导致气道平滑肌的肌源性表型（ASM）细胞是特异性的，具有分子和功能EL仅在男性中。 Wnt拮抗剂，可以脱离和或或或或或或或或或或或或或或或或或或反向认为由尼古丁诱导的表皮性特异性分子和功能效应确定，我们建议检查1）转播（TG）透射的机械基础，and and 2）围产期NIC诱导的后代肺高反应表型的性别特异性在AIM 1 Otine暴露引起的肺表型中是通过男性与女性生殖的（AIM 1A）（是否会受到父母的遗传多样性的影响（AIM 1B）（AIM 1B）在男性中观察到的明显的围产期尼古丁暴露于男性的肺部表型是否由男性ASM细胞的差异PKC表达和激活确定）。围产期尼古丁 - 尼古丁 - 纽约汀 - 纽约汀 - 纽约定 - 肺部肌源性表型的传播（AIM 3B）。 使用这种全面的细胞 - 分子 - 景观方法来解释孕产妇的基本机制，而不是在ONT上。 CLD的潜在风险，为研究TG对其他环境暴露的影响的分子机制铺平了道路。