Chronic inflammation is a major component of periodontitis, and while several tissue engineering and regeneration strategies have been identified that may be able to reverse the destructive effects of periodontitis their utility is likely compromised by the hostile microenvironment characteristic of the chronic inflammatory state. Dendritic cells (DCs) are the conductors of the immune system, and they may provide an appropriate target to manipulate and redirect the immune response to provide a non-inflammatory and non-destructive local environment. This application is based on the hypothesis that a material system providing appropriate spatiotemporal presentation of cues can locally control DC activation in order to bias the immune response towards a non-inflammatory phenotype, and dramatically enhance the effectiveness of bone inducing molecules carried by the same material system. This hypothesis will be examined with the following set of specific aims: (1) Materials systems will be developed to recruit host DCs and promote their activation towards a non-inflammatory phenotype, (2) Examine the ability of materials that recruit and program large numbers of tolerogenic DCs to promote regulatory T-cell differentiation and mediate inflammation in rodent models of periodontitis, and (3) Plasmid DNA encoding BMP-2 will be delivered from the material system that suppresses inflammation, to test whether reducing inflammation via DC targeting can enhance the effectiveness of inductive approaches to regenerate alveolar bone in rodent models of periodontitis. Successful completion of these aims will provide new materials that function to first modulate the inflammation-driven progression of periodontal disease, and then actively promote regeneration after successful suppression of inflammation. We envision the material and knowledge resulting from these studies can readily be translated into new materials for guided tissue regeneration (GTR) that actively regulate local immune and tissue rebuilding cell populations in situ. More broadly, inflammation is a component of many other clinical challenges in dentistry and medicine, and the general strategy pursued in this project could have wide utility in treating many of these diseases characterized by inflammation-mediated tissue destruction. Further, the material systems are also likely to provide novel and useful tools for basic studies probing DC trafficking, activation, T-cell differentiation, and the relation between the immune system and inflammation.
Periodontal disease afflicts millions of Americans. New therapies that can both stop the chronic inflammation characterizing this disease, and subsequently promote regeneration of the lost bone tissue could benefit many of these patients.
|Huebsch, Nathaniel; Kearney, Cathal J; Zhao, Xuanhe et al. (2014) Ultrasound-triggered disruption and self-healing of reversibly cross-linked hydrogels for drug delivery and enhanced chemotherapy. Proc Natl Acad Sci U S A 111:9762-7|
|Chan, Gail; Mooney, David J (2013) Ca(2+) released from calcium alginate gels can promote inflammatory responses in vitro and in vivo. Acta Biomater 9:9281-91|
|Chang, Jia; Liu, Fei; Lee, Min et al. (2013) NF-*B inhibits osteogenic differentiation of mesenchymal stem cells by promoting *-catenin degradation. Proc Natl Acad Sci U S A 110:9469-74|
|Li, Weiwei Aileen; Mooney, David J (2013) Materials based tumor immunotherapy vaccines. Curr Opin Immunol 25:238-45|
|Silva, Marcelo J B; Kajiya, Mikihito; AlShwaimi, Emad et al. (2012) Bacteria-reactive immune response may induce RANKL-expressing T cells in the mouse periapical bone loss lesion. J Endod 38:346-50|
|Lee, Kuen Yong; Mooney, David J (2012) Alginate: properties and biomedical applications. Prog Polym Sci 37:106-126|
|Malhotra, Deepali; Fletcher, Anne L; Astarita, Jillian et al. (2012) Transcriptional profiling of stroma from inflamed and resting lymph nodes defines immunological hallmarks. Nat Immunol 13:499-510|
|Franco, Gilson C N; Kajiya, Mikihito; Nakanishi, Tadashi et al. (2011) Inhibition of matrix metalloproteinase-9 activity by doxycycline ameliorates RANK ligand-induced osteoclast differentiation in vitro and in vivo. Exp Cell Res 317:1454-64|
|Lin, Xiaoping; Han, Xiaozhe; Kawai, Toshihisa et al. (2011) Antibody to receptor activator of NF-?B ligand ameliorates T cell-mediated periodontal bone resorption. Infect Immun 79:911-7|
|Giro, Gabriela; Coelho, Paulo G; Sales-Pessoa, Roberto et al. (2011) Influence of estrogen deficiency on bone around osseointegrated dental implants: an experimental study in the rat jaw model. J Oral Maxillofac Surg 69:1911-8|
Showing the most recent 10 out of 17 publications