The candidate is a dual-trained periodontist scientist who is committed to an academic career dedicated to study periodontal disease and improve oral health. Periodontitis is a polygenetic, inflammatory response towards bacterial pathogens at the gingival surface and affects 47% of the adult population in the United States. This common oral disease, without effective management, eventually leads to tooth loss and is significantly associated with systemic conditions such as diabetes. Analysis of a Genome Wide Association Study (GWAS) for periodontitis has identified Tumor necrosis factor Receptor-Associated Factor 3 Interacting Protein 2 (TRAF3IP2) as a target gene of interest. TRAF3IP2 dysfunction, such as induced by key genetic variants, is significantly associated with a periodontal inflammation phenotype defined by a high pathogen burden in plaque and local inflammation.TRAF3IP2 is a non-redundant adaptor molecule in the IL-17 pathway, which plays a critical role in mucosal defense. The objective of this research proposal is to acquire knowledge of the TRAF3IP2-mediated IL-17 response in gingival barrier defense mechanisms and the variant-induced functional defects in the IL-17 pathway. The candidate hypothesizes that loss of TRAF3IP2-IL17 signaling compromises the oral epithelial barrier and mucosal inflammatory signature and promotes dysbiotic microbiome overgrowth. This hypothesis will be tested by both in vitro and in vivo genetic approaches. Using Traf3ip2 ablated mice, the candidate will first determine the role of the IL-17/TRAF3IP2 pathway-modulated immune response and microbial community structure in a periodontal pathogen-induced murine alveolar bone loss model (Aim1). The candidate will then investigate the role of the IL-17/TRAF3IP2 pathway in mucosal physical barrier function and mechanism of IL-17-regulated tight junction structure (Aim 2). The candidate will further determine the TRAF3IP2 variant effect on immune response as reflected by the transcriptional and post-transcriptional regulation of chemokine synthesis and barrier function in genetically engineered, human gingival epithelial cells (Aim 3). The implementation of this research proposal requires additional training including complex microbial community structure analysis, Th17/IL-17 immunobiology, epithelial biology and molecular genomics. Strong mentorship by experts in each field and the exceptional environment at the University of North Carolina at Chapel Hill will foster the accomplishment of this research proposal and expedite the career development of the candidate. The scientific component and training outlined in this proposal provide a pathway to achieving not only the candidate's short-term goal, which is to transition into an independent investigator at a tenure track faculty position with R01 funding support, but also the long-term goal, which is to update understanding of host-pathogen interactions at the mucosal surface. The expertise gained will facilitate the development of novel preventive, diagnostic and therapeutic means to tackle periodontal disease and improve oral health.

Public Health Relevance

Periodontitis is a polygenetic inflammatory response towards a dysbiotic plaque bacterial flora, and affects 64.7 million adult U.S. population. The goal of this proposal is to determine the role of TRAF3IP2 mediated IL-17 pathway in the cross-talk between microbial community and host barrier defense mechanism involved in periodontitis, and to assess the TRAF3IP2 variant induced immune and barrier functional change in gingival epithelial cells. Understanding these mechanisms and dissecting the genetic role of periodontitis, which is the leading cause of tooth loss, may update the preventive and treatment options for this prevalent inflammatory disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Transition Award (R00)
Project #
4R00DE027086-03
Application #
9923812
Study Section
Special Emphasis Panel (NSS)
Program Officer
Chander, Preethi
Project Start
2019-07-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Iowa
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242