The effect of cortisol on tooth development

项目摘要/摘要 在怀孕期间，糖皮质激素应激激素皮质醇的过量水平被认为会显著改变 胎儿大脑网络，并导致长期的认知和行为问题。截至2019年，世界卫生组织 该组织认识到，全球有10%-20%的儿童和青少年经历过心理健康障碍。 如果没有适当的诊断和治疗，这些疾病会极大地影响儿童的发育和 削弱了他们过富有成效的生活的潜力。该领域的一个重大进步将是发现一种 生物传感器产生产前皮质醇暴露的生物标记物，这可能有助于未来的识别 心理健康障碍风险较高的个人。巧合的是，乳牙中的胎儿成釉细胞 在关键的胎儿大脑发育的同一窗口中，釉质基质被分解和矿化 在怀孕期间建立了网络，这使得成釉细胞成为生物传感器的候选细胞。一旦 釉质基质是产生的，它在发育、萌出和之后的过程中保持稳定的结构 乳牙脱落，使乳牙基质成为一个有希望的生物标志物来源。为了支持…… 这种可能性，我们实验室此前发现，乳牙采集自幼儿园的高唾液儿童 皮质醇的活性降低了牙釉质的厚度和密度。儿童皮质醇反应性与 胎儿期皮质醇水平升高。在这项提案中，我的目标是确定一组牙齿基质生物标记物 与产前皮质醇暴露增加有关，并确定成釉细胞是自然的机制 产前环境变化的生物传感器。因此，我将验证我的中心假设，即牙齿 保存永久的、可测量的皮质醇暴露记录，这是成釉细胞增殖改变和 在牙齿形成过程中成熟。我将使用以下具体目标来进行这些研究。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。 这些拟议的研究将使我能够识别牙齿基质生物标记物，这些生物标记物共同产生签名 用于增加产前皮质醇暴露。此外，本研究的结果将为今后的研究提供基础 研究成釉细胞如何从生物学上检测和记录其他产前环境应激源 已知会影响胎儿发育。这项拟议的研究计划，结合我的牙科临床培训，将 为我提供成为一名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.