The effect of cortisol on tooth development

项目概要/摘要 在怀孕期间，糖皮质激素应激激素皮质醇的过量水平， 胎儿的大脑网络，并导致长期的认知和行为问题。截至2019年，世界卫生组织 该组织承认，全世界有10-20%的儿童和青少年患有精神健康障碍。 如果没有适当的诊断和治疗，这些疾病会严重影响儿童的发育， 削弱了他们过上富有成效生活的潜力。该领域的一个重大进展将是发现一种 一种生物传感器，可产生产前皮质醇暴露的生物标志物，这可能有助于前瞻性识别 精神疾病风险更高的人。巧合的是，乳牙中的胎儿成釉细胞 在关键胎儿大脑的同一发育窗口期间，降低并矿化釉基质 在妊娠期间建立网络，使得成釉细胞成为生物传感器的有吸引力的候选者。一旦 釉质基质产生后，它在发育、萌出和之后的持续时间内保持稳定的结构。 乳牙脱落，使乳牙基质成为生物标志物的有希望的来源。支持 这种可能性，我们的实验室以前发现，从幼儿园儿童收集的乳牙， 皮质醇反应性降低了牙釉质的厚度和密度。儿童的皮质醇反应性与 产前皮质醇水平升高在本提案中，我的目标是确定一组牙齿基质生物标志物 与产前皮质醇暴露升高有关，并确定成釉细胞是天然的机制， 产前环境变化的生物传感器。因此，我将检验我的中心假设， 存储由于成釉细胞增殖改变而导致的皮质醇暴露的永久的、可测量的记录， 牙齿形成过程中的成熟。我将在这些研究中使用以下具体目标。目标1：确定 与皮质醇反应性增加相关的牙齿物理测量小组。目标2：识别细胞 皮质醇影响牙齿形态和釉质矿化的机制。 这些拟议中的研究将使我能够确定牙齿基质生物标志物，共同产生一个签名， 产前皮质醇暴露量增加此外，本研究的结果将为未来的研究提供基础。 研究成釉细胞如何从生物学上检测和记录其他产前环境压力 已知会影响胎儿发育这一拟议的研究计划，结合我的牙科临床培训，将 为我提供成为独立调查员所需的技能和经验。

PROJECT SUMMARY / ABSTRACT During pregnancy, excess levels of the glucocorticoid stress hormone, cortisol, is known to significantly alter fetal brain networks and result in long-term cognitive and behavioral problems. As of 2019, the World Health Organization recognizes 10-20% of children and adolescents experience mental health disorders worldwide. Without proper diagnosis and treatment, these conditions dramatically impact the child’s development and impairs their potential to live a productive life. A significant advance for the field would be the discovery of a biosensor that produces biomarkers of prenatal cortisol exposure, which may aid in the prospective identification of individuals with a higher risk of mental health disorders. Coincidentally, fetal ameloblasts in primary teeth lay down and mineralize the enamel matrix during the same developmental window in which critical fetal brain networks are established during gestation, making ameloblasts attractive candidates for biosensors. Once the enamel matrix is produced, it remains a stable structure for the duration of development, eruption, and after shedding of the primary tooth, making the primary tooth matrix a promising source of biomarkers. In support of this possibility, our lab previously found that primary teeth collected from kindergarten children with high salivary cortisol reactivity have reduced tooth enamel thickness and density. Cortisol reactivity in children is associated with increased levels of prenatal cortisol. In this proposal, I aim to determine a panel of tooth matrix biomarkers related to elevated prenatal cortisol exposure, and to identify the mechanisms by which ameloblasts are natural biosensors of alterations in the prenatal environment. Therefore, I will test my central hypothesis that teeth store permanent, measurable records of cortisol exposure as a result of altered ameloblast proliferation and maturation during tooth formation. I will use the following specific aims for these studies. Aim 1: Determine a panel of physical tooth measurements associated with increased cortisol reactivity. Aim 2: Identify the cellular mechanisms by which cortisol affects tooth morphology and enamel mineralization. These proposed studies will allow me to identify tooth matrix biomarkers that, collectively, produce a signature for increased prenatal cortisol exposure. In addition, results from this study will provide the foundation for future studies to investigate how ameloblasts can biologically detect and record other prenatal environmental stressors known to impact fetal development. This proposed research plan, combined with my dental clinical training, will provide me with the skills and experience I need to become an independent investigator.