Direct Effects of Nicotine on Cranial Growth and Development

尼古丁对颅骨生长和发育的直接影响

• 批准号: 9544921
• 负责人: James J. Cray
• 金额: $ 11.7万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9544921
• 关键词: Affect; Agonist; Animals; Apoptosis; Area; Autophagocytosis; Biochemical; Biological Assay; Birth; Bupropion; Calvaria; Cell Cycle; Cell Differentiation process; Cells; Cellular Metabolic Process; Centers for Disease Control and Prevention (U.S.); Cephalic; Cephalometry; Cigarette; Comorbidity; Congenital Abnormality; Cotinine; Craniofacial Abnormalities; Craniosynostosis; Data; Deformity; Detection; Development; Diagnosis; Dose; Electronic cigarette; Evaluation; Female; Fetal Development; Fetus; First Pregnancy Trimester; Flow Cytometry; Future; Genetic Transcription; Growth; Growth and Development function; Harvest; Histologic; Homeostasis; In Vitro; Incidence; Individual; Infant; Intracranial Hypertension; Investigation; Joints; Knockout Mice; Knowledge; Lactation; Length; Link; Live Birth; MAP Kinase Gene; Measurable; Measures; Medical; Mental Retardation; Modeling; Mus; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Nicotinic Receptors; Osteogenesis; Pathway interactions; Perinatal; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Predisposition; Pregnancy; Pregnant Women; Prevalence; Proto-Oncogene Proteins c-akt; Protocols documentation; Psychotropic Drugs; Public Health; Quantitative Reverse Transcriptase PCR; Receptor Cell; Regimen; Regulation; Research; Risk; Role; Route; Safety; Sampling; Serum; Severities; Site; Skeleton; Small Interfering RNA; Smoke; Smoking; Surgical sutures; System; Technology; Time; Tobacco use; Wild Type Mouse; Woman; Work; acetylcholine receptor agonist; cigarette smoking; clinically relevant; craniofacial; craniofacial development; craniofacial tissue; cranium; experimental study; fetal; gain of function; in utero; in vivo; mouse model; neurosurgery; nicotine exposure; nicotine replacement; nicotine use in pregnancy; nicotine vapor; offspring; postnatal; pre-clinical; premature; prenatal exposure; protein expression; pup; receptor; receptor expression; senescence; varenicline

Here we seek to understand the direct effects of fetal and postnatal nicotine exposure on craniofacial growth and development. This area is significant as our knowledge of the concomitant effects of cigarettes have been well studied for birth defects, but little work has focused on the individual components such as nicotine. Electronic cigarettes have now entered the market without regulation and are being marketed as safe. As ~11% of pregnant women continue to smoke during pregnancy, electronic cigarettes or nicotine replacement therapies may be viewed as a safer alternative to cigarette smoking. However, our understanding of the effects of nicotine, the common component between cigarettes, electronic cigarettes, and nicotine replacement therapies, on the developing fetus, specifically the craniofacial skeleton, is poor. Smoking has been linked to an increased risk for the craniofacial birth defect, craniosynostosis. Craniosynostosis occurs in 1:1800-2500 live births and can present with a myriad of medical comorbidities including ocular proptoses, increased intracranial pressure, alter cranial volume, and mental retardation. Most diagnosed cases require neurosurgery to correct the deformity and restore normal growth trajectories. It is unknown if nicotine alone increases the risk for craniosynostosis, but nicotinic receptors have recently been identified within the growth sites of the calvaria (sutures). Here we aim to determine the effects of in utero and postnatal nicotine exposure in a dose by time of exposure manner to elucidate 1) if nicotine can alter craniofacial growth; 2) if there is a segregating effect by dose; and 3) if there is a window of susceptibility during which the fetus or infant would be most susceptible to these effects. The two areas of investigation of this project are: 1) Characterize the effect of in utero and postnatal (lactation) nicotine exposure on craniofacial growth. We will utilize our preclinical craniofacial growth model to determine the effects of nicotine in a dose by time manner. As we have previously identified nicotinic receptors within the growth sites of the skull we anticipate that increasing dose and time of exposure will result in measurable alterations in growth in our fetal and post-natal exposed animals. 2) Define the effects of nicotine on the cells of the cranial growth sites, the sutures. Nicotine is a potent stimulant drug known to have effects on cell metabolism. Here we will utilize cells garnered from the suture to determine the specific effect (proliferation, apoptosis, autophagy, osteogenesis, senescence) precipitated by nicotine exposure. In addition, we will determine the effect on nicotinic receptor expression a direct target of nicotine exposure.

在这里，我们试图了解胎儿和出生后尼古丁暴露对颅面生长的直接影响， 发展这一领域是重要的，因为我们对香烟的伴随影响的了解已经很好了。 研究出生缺陷，但很少有工作集中在个别成分，如尼古丁。电子 香烟现在已经不受管制地进入市场，并以安全的名义销售。约11%的孕妇 女性在怀孕期间继续吸烟，电子烟或尼古丁替代疗法可能会 被认为是吸烟的更安全的替代品。然而，我们对尼古丁影响的理解， 香烟、电子香烟和尼古丁替代疗法之间的共同成分， 发育中的胎儿，特别是颅面骨骼，很差。吸烟与以下疾病的风险增加有关： 颅面先天缺陷颅缝早闭颅缝早闭发生在1：1800-2500活产婴儿中， 存在多种医学合并症，包括眼球突出、颅内压升高、改变 颅容量和智力迟钝大多数确诊病例需要神经外科手术来矫正畸形， 恢复正常的增长轨迹。目前尚不清楚尼古丁是否单独增加颅缝早闭的风险， 最近已经在颅顶（缝）的生长部位内鉴定出烟碱受体。我们的目标是 通过暴露时间方式确定子宫内和出生后尼古丁暴露剂量的影响， 阐明1）尼古丁是否可以改变颅面生长; 2）是否存在剂量隔离效应; 3）是否存在 胎儿或婴儿最易受这些影响的敏感窗口。 该项目的两个调查领域是： 1)描述子宫内和产后（哺乳期）尼古丁暴露对颅面生长的影响。 我们将利用我们的临床前颅面生长模型，以确定尼古丁的影响，在一个剂量的时间 方式正如我们先前在头骨的生长部位鉴定出烟碱受体，我们预期， 增加剂量和暴露时间将导致我们的胎儿和出生后生长的可测量的变化， 暴露的动物 2)确定尼古丁对颅骨生长部位细胞的影响，缝合。 尼古丁是一种强效兴奋剂，已知对细胞代谢有影响。在这里我们将利用细胞获得 以确定特定效应（增殖、凋亡、自噬、骨生成、衰老） 是由尼古丁引起的此外，我们还将确定尼古丁受体表达的影响， 尼古丁暴露的直接目标。