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（由申请人提供）：本申请是对NHLBI TOSI HL-131的回应：发育中的肺暴露于香烟烟雾是发生慢性肺病（CLD）的独立风险因素，包括晚年的哮喘。甚至更重要的是，最近已经表明，通过改变胎儿肺发育所必需的特定发育信号传导途径，围产期尼古丁暴露相关CLD风险不仅限于尼古丁暴露的后代，而且还通过转代方式传递给随后未暴露后代的后代（Rehan et al，AJP Lung; 2013;305：L501-7）。具体而言，尼古丁通过刺激Wnt通路，抑制PPAR γ信号传导，改变发育中肺中间充质细胞的正常分化，导致气道平滑肌（ASM）细胞的肌源性表型。有趣的是，这些效应具有性别特异性，对ASM细胞的分子和功能效应仅见于雄性。重要的是，作为有效的Wnt拮抗剂的PPAR β激动剂可以抑制和/或逆转这些作用。假设这些效应是由尼古丁诱导的性腺生殖系表观遗传变化决定的，这导致肺特异性分子和功能效应，我们建议检查1）跨代（TG）传递和2）围产期尼古丁暴露诱导后代肺高反应表型的性别特异性的机制基础。在目标1中，我们将确定围产期尼古丁暴露诱导的肺表型是否通过男性与女性生殖系传播（目标1A），是否受父母遗传多样性的影响（目标1B），以及在儿童期观察到的肺表型是否也在成年期观察到（目标1C）。在目标2中，我们将确定在男性中观察到的更明显的围产期尼古丁暴露诱导的肺表型是否由男性与女性ASM细胞中的差异PKC表达和活化决定（目标2A），以及是否通过阻断相关的特定PKC亚型来消除（目标2B）。在目标3中，我们将确定围产期尼古丁诱导的生殖系和ASM表观遗传变化是否从F1代传递到F3代（目标3A），以及使用PPAR β激动剂罗格列酮同时抑制尼古丁诱导的Wnt激活是否阻断这些表观遗传变化并防止围产期尼古丁诱导的肺肌原性表型TG传递（目标3B）。该提案中提出的概念是全新的和创新的，因此通过解决 基本的机制，解释了母亲吸烟不仅对暴露的后代，而且对随后的许多代的有害影响。使用这种全面的细胞-分子-表观遗传学方法，拟议的研究不仅可能产生新的关键分子数据，这些数据可能会显著影响我们对CLD发病机制的理解，而且还提供了CLD风险的新机制信息，为研究TG对其他环境暴露的分子机制铺平了道路。