. The objective of our parent R01 grant (DE025255) is to determine the mechanism of B10-mediated inhibition of inflammation and periodontal bone resorption in periodontal disease. So far, our data have demonstrated that promoting local B10 function is achievable and that antigen specificity is required for the local infiltration of B10 cells. We are currently investigating the immune regulatory components that relay the ultimate function of B10 activation, in the context of immune cell-cell interaction, and how changes in such interactions may affect disease outcome. Such information is important because it allow us to design optimal strategies to synergize immune regulatory function to restore health and minimize untoward side effects of immune activation/inhibition. However, we realized the challenge to achieve these goals due to the lack of required expertise and resources at our hands. To overcome such challenge, we will take advantage of the newly established collaboration between the PI and Dr. Corneliu Sima, Assistant Professor at Harvard School of Dental Medicine. Dr. Sima is an early stage Investigator (ESI) with expertise in monocyte/macrophage biology and has developed optimized intravital gingival microscopy assays for assessment of leukocyte recruitment and phenotype in periodontal disease. Together with the in vivo imaging system (IVIS), we will be able to detect and trace local interactions between B10 and macrophages in gingival tissues. Our hypothesis is that B10 activation promotes macrophage activation toward a regulatory/anti-inflammatory and pro-resolving phenotype, which contribute to the reduced inflammation and bone loss. To test this hypothesis, we will first determine the effect of activated B10 cells on Macrophage phenotype in vitro using a cell co-culture system (Aim 1). Then we will investigate the Macrophage phenotype switching and gingival inflammation after adoptive B10 transfer using IVIS and intravital microscopy (Aim 2). In summary, the points aligned with the goal of this FOA are the following: 1. This proposal is a collaboration with an ESI to explore novel mechanism of synergistic interaction between innate (Dr. Sima) and adaptive immunity (Dr. Han). 2. Extend our hypothesis and utilize techniques unavailable to PI of the parent R01, which is an important enhancement within the scope of the original Aims. 3. Take advantage of the cutting-edge cell imaging technologies with high sensitivity and resolution to fill the gap of precision imaging of oral lesions used in immunology research. 4. If successful, it will benefit both collaborative investigators for future R01 applications. 5. The collaborators in the proposal don't have any past record of collaboration. 6. No proposed salary allocation for PIs from this fund.
This proposed supplemental work is valuable to broaden our insights into the mechanism of B10- mediated immune regulation in periodontal disease. It is expected to generate important new information of B10-macrophage interaction and their reciprocal functionality, which would not be possible without this collaboration and will benefit the research programs of both collaborators. The proposed IVIS and intravital microscopy allow us to track immune cell trafficking and physical interaction in vivo with high anatomical details, which bring together an innovative imaging method for the assessment of immune responses in a systematic way.
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