Although infection of the dental pulp induces a periapical lesion, the course of this disease is also affected by host factors. For example long duration diabetics exhibited teeth with larger periapical lesions than short duration diabetics and healthy controls. To date, the relationships between bacterial pathogens/pathogen- associated molecular patterns (PAMPs) and the host immune system have been extensively investigated. However involvement of host-derived danger-associated molecular patterns (DAMPs), which are released by damaged cells, in periapical lesions is unknown. In our preliminary studies, SAA3 (Serum Amyloid A3), which is a DAMP, was the most highly up-regulated gene in rodent periapical lesions, and the SAA3 protein was strongly expressed in mouse periapical lesions. Systemic SAA levels are significantly elevated in a mouse diet-induced obesity model (DIO), in which animals develop pre-diabetes and steatosis (fatty liver) vs. control mice, indicating an association of SAA with obesity- induced systemic inflammation. In addition, infected DIO mice exhibited elevated serum SAA and had larger periapical lesions compared to controls, suggesting a pathologic link between SAA and periapical lesion severity. The central hypothesis of this proposal is that SAA, produced in response to dental infections, exacerbates dentoalveolar bone destruction, and furthermore contributes to systemic inflammation and its sequellae in obesity/type 2 diabetes. We propose that SAA is the primary DAMP in periapical lesions, and is a key enhancer of dentoalveolar inflammation. SAA is therefore an innovative target in modulating oral infection and inflammation. We will pursue the role of SAA in periapical lesions in the following three specific aims:
AIM 1 : To assess the role of SAAs in periapical lesions using SAA knockout (KO) and overexpression mouse models.
Aim 2 : To identify the functional receptors and signaling pathways for SAAs.
AIM 3 : To determine whether obesity-diabetes ('diabesity') alters periapical inflammation via SAAs.
This project will determine the functional role of serum amyloid A (SAA) in periapical lesions. We also will investigate the role of SAA in the link between local periapical inflammation and diabesity-induced systemic inflammation. The outcomes will be important and useful for the development of novel SAA-targeted therapeutics.
|Rider, Daniel; Furusho, Hisako; Xu, Shuang et al. (2016) Elevated CD14 (Cluster of Differentiation 14) and Toll-Like Receptor (TLR) 4 Signaling Deteriorate Periapical Inflammation in TLR2 Deficient Mice. Anat Rec (Hoboken) 299:1281-92|
|Sasaki, Hajime; Hirai, Kimito; Martins, Christine M et al. (2016) Interrelationship Between Periapical Lesion and Systemic Metabolic Disorders. Curr Pharm Des 22:2204-15|