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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE019917-05
Application #
8484820
Study Section
Special Emphasis Panel (ZDE1-RW (11))
Program Officer
Lumelsky, Nadya L
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$631,384
Indirect Cost
$90,370
Name
Harvard University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Movila, Alexandru; Kajiya, Mikihito; Wisitrasameewong, Wichaya et al. (2018) Intravital endoscopic technology for real-time monitoring of inflammation caused in experimental periodontitis. J Immunol Methods 457:26-29
Ishii, Takenobu; Ruiz-Torruella, Montserrat; Ikeda, Atsushi et al. (2018) OC-STAMP promotes osteoclast fusion for pathogenic bone resorption in periodontitis via up-regulation of permissive fusogen CD9. FASEB J 32:4016-4030
Hondroulis, Evangelia; Movila, Alexandru; Sabhachandani, Pooja et al. (2017) A droplet-merging platform for comparative functional analysis of m1 and m2 macrophages in response to e. coli-induced stimuli. Biotechnol Bioeng 114:705-709
Hirschfeld, Josefine; Howait, Mohammed; Movila, Alexandru et al. (2017) Assessment of the involvement of the macrophage migration inhibitory factor-glucocorticoid regulatory dyad in the expression of matrix metalloproteinase-2 during periodontitis. Eur J Oral Sci 125:345-354
Kanzaki, Hiroyuki; Movila, Alexandru; Kayal, Rayyan et al. (2017) Phosphoglycerol dihydroceramide, a distinctive ceramide produced by Porphyromonas gingivalis, promotes RANKL-induced osteoclastogenesis by acting on non-muscle myosin II-A (Myh9), an osteoclast cell fusion regulatory factor. Biochim Biophys Acta Mol Cell Biol Lipids 1862:452-462
Verbeke, Catia S; Gordo, Susana; Schubert, David A et al. (2017) Multicomponent Injectable Hydrogels for Antigen-Specific Tolerogenic Immune Modulation. Adv Healthc Mater 6:
Wisitrasameewong, W; Kajiya, M; Movila, A et al. (2017) DC-STAMP Is an Osteoclast Fusogen Engaged in Periodontal Bone Resorption. J Dent Res 96:685-693
Yamaguchi, Tsuguno; Movila, Alexandru; Kataoka, Shinsuke et al. (2016) Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis. Infect Immun 84:2802-12
Kanzaki, Hiroyuki; Shinohara, Fumiaki; Suzuki, Maiko et al. (2016) A-Disintegrin and Metalloproteinase (ADAM) 17 Enzymatically Degrades Interferon-gamma. Sci Rep 6:32259
Movila, Alexandru; Mawardi, Hani; Nishimura, Kazuaki et al. (2016) Possible pathogenic engagement of soluble Semaphorin 4D produced by ??T cells in medication-related osteonecrosis of the jaw (MRONJ). Biochem Biophys Res Commun 480:42-47

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