A periapical lesion is an infection-induced inflammation within the jaws that ultimately results in the destruction of bone that surrounds the apex of the tooth root. Periapical lesions are often refractory to treatment and require retreatments or, in worst case, tooth extraction. Thus, there is an acute need for novel therapeutic approaches that improve the healing of periapical lesions. The long-term goal of this project is to identify the molecular networks that regulate wound healing after infection-induced inflammation and bone destruction. Our preliminary studies showed that the Toll-like receptor 2 (TLR2)/Interleukin-10 (IL-10) double deficient (dKO) mouse infected with common endodontic pathogens exhibits an acute periapical lesion that subsequently exhibiting spontaneous wound healing principally bone regeneration The healing response present in dKO mice is strongly associated with up-regulation of HIF-1a (hypoxia inducible factor 1 alpha) expression in the lesion and sequential activation of proinflammatory M1 and anti-inflammatory M2 macrophages. These findings suggest that HIF-1a activation is a key element for improved periapical wound healing. The central hypothesis of this proposal is that HIF-1a activation leads to periapical wound healing via induction of M1 macrophage activation followed by emergence of M2 to facilitate final clearance of the lesion. Conversely, failure of HIF-1a activation results in failue of M1 activation followed by delayed and polarized M2 macrophage activation, which leads to chronic inflammation and radicular granuloma. Thus, the HIF-1a- mediated response is a target pathway for the development of novel therapeutics for improving periapical wound healing. The overall goal of this exploratory proposal is to determine whether HIF-1a activation will predictably induce periapical lesion in immunocompetent (WT) mice. The goal will be achieved through two specific aims.
AIM 1 is to assess the impact of HIF-1a modulation on periapical lesion formation and healing in WT mice. Lentiviral vectors coding HIF-1a shRNA and constitutively active form of HIF-1a will be used to modulate HIF-1a activity.
AIM 2 is to determine the role of endogenous HIF-1a on macrophage activation and phenotype in vivo. HIF-1a will be inactivated in dKO mice, and endogenous HIF-1a will activated by chemically inhibiting prolyl hydroxylase that is essential for HIF-1 activation in order to measure the effect on macrophage activation and the course infection. The proposed studies will provide new information about the fundamental role HIF-1a in periapical lesions, which is a novel wound healing pathway that involves M1/M2 sequential macrophage activation, and demonstrate a therapeutic potential of HIF-1a in dentoalveolar inflammation. These outcomes are targeted to novel treatment strategies to improve the healing process in dentoalveolar infections that will have potential application in other chronic fibrotic and granulomatous diseases.

Public Health Relevance

The successful rate of root canal treatment in cases with pre-operative periapical lesions (root canal diseases) is always lower than that in cases without the lesions, indicating a needs of novel approaches to improve the treatment outcomes. This application will investigate the role of HIF-1a (hypoxia inducible factor-1 alpha subunit) in the healing of periapical lesions. Successful completion of these studies will identify a novel periapical wound healing mechanism mediated by HIF-1a and suggest its therapeutic potential in endodontics.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Exploratory/Developmental Grants (R21)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lumelsky, Nadya L
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Forsyth Institute
United States
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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