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...