Association between early Candida infection (oral thrush) and severe early childhood caries

项目摘要 拟议的K23职业发展奖在临床和转化研究将形成一个基础博士。 Yuan Liu将成为一名独立的临床医生-科学家，拥有严重幼儿龋齿（S-ECC）的专业知识。 K23培训目标按顺序进行，并将支持她发展关键专业知识 在3个领域：1）发展设计和进行临床研究的先进技能; 2）获得先进的 真菌生物学和微生物组学的知识和方法; 3）改善科学交流， 技能和网络。候选人将获得指导纵向研究和基本培训的经验 通过利用宾夕法尼亚大学的广泛资源， 跨学科指导委员会，在临床研究，流行病学， 生物工程、微生物组和生物信息学。S-ECC是一个主要的公共卫生问题，其特征在于 口腔微生物的失调负担，导致幼儿牙齿上的持久性和毒性生物膜， 严重的蛀牙这个过程不仅破坏了牙列，而且还可能对牙齿产生负面影响。 一般健康，如复杂的系统性感染，以及幼儿的福祉。新出现的临床 有证据表明白色念珠菌在S-ECC中的潜在作用。此外，我们的回顾性研究 使用来自六家主要儿童医院的电子健康记录（EHR）显示， 在12个月以下的幼儿中检测到口咽念珠菌病（OPC）， 不久之后，特别是在13至36个月之间，龋齿发生。然而，只有跨- 到目前为止，已经进行了部分人体研究。纵向研究是必要的，以更好地评估 幼儿OPC和S-ECC之间的因果关系。与此同时，还需要进一步的研究来确定 真菌在龋病中的作用，以及口腔中念珠菌定植是否可以作为S-ECC风险的可靠临床标志。 为了解决这个问题，拟议的研究将集中在进行为期2年的前瞻性纵向研究， 研究早期OPC与S-ECC进展之间的关系，以及念珠菌对S-ECC的影响。 功能菌斑微生物组上的定殖和生物膜毒力。刘博士将研究3个具体目标： (1)检查婴儿队列中早期OPC和S-ECC发展之间的关联;（2）评估 OPC和念珠菌定植对婴儿菌斑微生物组的影响;（3）研究念珠菌在 对生物膜致龋特性的影响。临床和翻译工作的结果将进一步阐明 OPC和S-ECC之间的联系，并加强对真菌致病机理的理解 关于S-ECC总的来说，这些结果将为未来的机制临床研究提供机会， 制定预防S-ECC的有针对性的策略。K23奖将为刘博士提供新的知识， 作为临床科学家，她的职业目标必不可少的领域，实施拟议的研究计划，并建立 一个独立的研究计划，目标是在K23奖项结束之前获得R 01。

PROJECT SUMMARY The proposed K23 career development award in clinical and translational research will form a foundation for Dr. Yuan Liu to become an independent clinician-scientist, with expertise on severe early childhood caries (S-ECC). The K23 training objectives progress in a sequential fashion and will support her development of key expertise in 3 areas: 1) developing advanced skills in designing and conducting clinical studies; 2) acquiring advanced knowledge and methods in fungal biology and microbiome; 3) improving scientific communication, grant writing skills and networking. The candidate will acquire experience in directing longitudinal study and essential training by making the use of the extensive resources at the University of Pennsylvania and capitalizing on an interdisciplinary mentoring committee with broad, complementary expertise in clinical research, epidemiology, bioengineering, microbiome, and bioinformatics. S-ECC is a major public health problem characterized by dysbiotic oral microbial burden leading to a persistent and virulent biofilm on the teeth of toddlers that causes rampant tooth decay. This process not only destroys the dentition but can also have a negative impact on the general health, such as complicated systemic infections, and the well-being of young children. Emerging clinical evidence has spotlighted the potential role of Candida albicans in S-ECC. Furthermore, our retrospective study using electronic health records (EHR) from six major children’s hospitals revealed that, oral thrush (oropharyngeal candidiasis or OPC) detection in toddlers less than 12 months of age was strongly associated with the development of dental caries soon after, particularly between 13 and 36 months. However, only cross- sectional human studies have been performed thus far. Longitudinal studies are warranted to better assess the causal association between OPC and S-ECC in toddlers. In parallel, further studies are needed to determine the fungal role in caries and if Candida colonization in oral cavity could be a reliable clinical marker for risk of S-ECC. To address this, the proposed research will be focused on conducting a 2-year prospective longitudinal study to investigate the association between early OPC and the progression of S-ECC, and the impact of Candida colonization on the functional plaque microbiome and biofilm virulence. Dr. Liu will investigate 3 specific aims: (1) examine the association between early OPC and S-ECC development in a cohort of infants; (2) evaluate the influence of OPC and Candida colonization on the plaque microbiome in infants; (3) study the role of Candida on biofilm cariogenic properties. Results from this clinical and translational effort will further elucidate the causal link between OPC and S-ECC, and enhance the understanding of fungal contributions to the etiopathogenesis of S-ECC. Collectively, these results will provide future opportunities for mechanistic clinical studies and developing targeted strategies for preventing S-ECC. This K23 award will provide Dr. Liu with new knowledge in the areas essential to her career goals as a clinician-scientist, implement the proposed research plan and build an independent research program with the goal of receiving an R01 prior to the end of the K23 award.