Genomic and bioinformatic approaches for understanding the effects of childhood adversity on primary tooth formation and caries development in young children

项目摘要。这个短期指导职业提升奖在牙科，口腔，和 职业中期和高级研究者（K18）的颅面（DOC）研究将提供候选人 有受保护的时间来获得技能和知识，以扩大她的研究计划，包括 DOC概念。PI是一个成熟的研究者，研究遗传，表观遗传和社会- 抑郁症的环境决定因素，重点是童年逆境在早期生活中的作用。 PI尚未接受任何正式的牙科开发培训，也没有任何DOC概念。她寻求 短期培训，学习测量牙齿发育和牙齿硬组织的概念和方法 表型，然后她将使用它来实现她的职业目标，研究 牙齿和大脑发育培训将由导师玛丽L博士监督。Marazita，国际 沿着有三位资深顾问，是公认的龋齿遗传学和其他DOC特征方面的专家。 培训将包括课程作业，在线研讨会，指导阅读，会议出席和实验 在两个研究中心（肯特大学和卡尔加里大学）的经验，这将提供与PI不同的培训 和导师的家乡机构。培训还将包括对中心研究的二次分析 在阿巴拉契亚的口腔健康研究（COHRA）。根据COHRA的一个项目（R 01-DE 014899） PD/PI Marazita，McNeil，Foxman，Shaffer）建立COHRA 2纵向出生队列并随访 来自北方阿巴拉契亚的1000名欧洲血统和250名非洲裔美国孕妇。的PI 将分析来自COHRA 2的现有数据，以调查遗传因素和儿童 暴露于母亲痛苦，一种常见的童年逆境，与龋齿（牙齿）有关 第一颗牙的年龄和第一颗牙的年龄。在目标1中，PI将使用大脑结构的生物信息学数据， 疾病来计算捕获多个基因的聚集效应的遗传风险分数（即，多基因 风险评分; PRS），然后检查它们对龋齿风险和第一颗牙齿出现时的年龄的作用。 在目标2中，PI将使用称为结构化生命过程建模方法的分析技术 （SLCMA），以评估重复测量数据如何影响儿童暴露于 母亲的痛苦（例如，全球和养育压力;抑郁症状）与 龋齿和乳牙萌出时间。K18的发现可能会导致识别 新的基因与龋齿和牙齿形成的时间，并增加知识的作用 产妇痛苦对这些牙科结果的影响，然后可以指导有针对性的预防干预措施。 建议的培训经验将确保PI学习概念和测量方法， 研究牙齿的形成，这样她就可以更深入地将这些概念融入她的研究。K18将 也可作为R 01提案的基础，该提案将复制和扩展此处调查的结果。

Project Summary. This Short-Term Mentored Career Enhancement Award in Dental, Oral, and Craniofacial (DOC) Research for Mid-Career and Senior Investigators (K18) will provide the candidate with the protected time to acquire the skills and knowledge to augment her research program to include DOC concepts. The PI is an established investigator who studies the genetic, epigenetic, and social- environmental determinants of depression, with a focus on the role of childhood adversity in early life. The PI has not yet received any formal training in dental development nor any DOC concept. She seeks short-term training to learn concepts and methods to measure tooth development and dental hard tissue phenotypes, which she will then use to achieve her career goal of studying the connections between tooth and brain development. Training will be overseen by mentor Dr. Mary L. Marazita, an internationally recognized expert in the genetics of caries and other DOC features, along with three senior advisors. Training will consist of coursework, on-line seminars, guided readings, conference attendance, and lab experiences at two sites (University of Kent and Calgary), which will provide training distinct from the PI’s and mentor’s home institutions. Training will also include a secondary analysis of a study from the Center for Oral Health Research in Appalachia (COHRA). Under one of COHRA’s projects (R01-DE014899 PD/PIs Marazita, McNeil, Foxman, Shaffer) the COHRA2 longitudinal birth cohort was built and followed 1000 European-ancestry and 250 African American pregnant women from northern Appalachia. The PI will analyze existing data from COHRA2 to investigate the extent to which genetic factors and children’s exposure to maternal distress, a common type of childhood adversity, associate with dental caries (tooth decay) and age at first tooth eruption. In Aim 1, the PI will use bioinformatics data on brain structures and disorders to calculate genetic risk scores capturing the aggregate effect of multiple genes (i.e., polygenic risk scores; PRS) and then examine their role on both dental caries risk and age at first tooth emergence. In Aim 2, the PI will use an analytic technique called the structured lifecourse modeling approach (SLCMA) to assess with repeated-measures data how the developmental timing of children’s exposure to maternal distress (e.g., global and parenting stress; depressive symptoms) associates with number of dental caries and primary tooth eruption timing. Findings from this K18 may lead to the identification of new genes associated with dental caries and tooth formation timing, and increase knowledge on the role of maternal distress on these dental outcomes, which could then guide targeted preventive interventions. The proposed training experiences will ensure the PI learns concepts and measurement approaches to study tooth formation so she can more deeply integrate these concepts into her research. This K18 will also serve as the basis for an R01 proposal that will replicate and extend findings investigated here.