Loss of inflammation regulation is a biological event common to many human chronic inflammatory diseases including Type II diabetes mellitus, and periodontitis. A return to homeostasis (resolution of inflammation) requires cellular activation of a well-coordinated process mediated by endogenous lipids, including, resolvin E1 (RvE1), derived from the ?-3 fatty acid, eicosapentaenoic acid (EPA). Activation of the G protein-coupled receptor, ChemR23, by the agonist ligand RvE1 is known to lead to attenuation of NF-KB mediated pro-inflammatory cytokines, dictating cellular fate and consequently resolution of inflammation. However, how ChemR23 in innate cells fails to activate resolution in chronic inflammatory diseases remains unclear. This proposal will test the hypothesis that ChemR23 expression and function are altered in chronic inflammatory diseases and that engineered agonist biomimetic antibodies to chemR23 can impact the inflammatory phenotype. To that end, four distinct but complementary specific aims are proposed. The mentored phase of the proposal will be carried out under Prof. Van Dyke at The Forsyth Institute. The goal of the K99 mentored phase is to: 1) characterize the expression of ChemR23 receptors on inflammatory cells (neutrophils and monocyte/macrophages) of subjects with Type II diabetes and/or periodontitis;2) characterize the molecular pathways that are regulated by ChemR23 in disease. This training will provide expertise in inflammation biology, clinical pathology and proteomics. The understanding of ChemR23 in dictating the path chronic inflammation diseases investigated during the mentored phase will provide the foundation for transition to independent phase. Inflammation resolution is a rapidly emerging field of interest that would greatly benefit from unexplored biomimetic approaches to therapeutically regulate cell fate. Building on previous experience, the goal of R00 independent phase is to: 3) engineer agonist monoclonal antibody for ChemR23, and 4) to characterize the cellular and molecular mechanisms by which therapeutic antibodies regulate inflammation through ChemR23 activation. This award includes a well-structured training program that provides course work and seminar learning experiences as well as ensuring protected research time during concurrent specialty training in Periodontology at Harvard School of Dental Medicine. Successful completion of this project will lead to better understanding of the molecular and cellular role of ChemR23, and to translate this knowledge for the development of agonist biomimetics to modulate inflammatory diseases clinically.
Despite advances in our knowledge of causes and risk factors associated with chronic inflammatory diseases such as diabetes type 2 and periodontitis, there are no signs of decline in prevalence. According to the American Diabetes Association (2011), 25.8 million children and adults have diabetes, and the CDC (2012) estimate that 64.7 million adults have periodontal disease. Inflammatory diseases such as type 2 diabetes and chronic periodontal diseases have a reciprocal relationship. Among the people diagnosed with diabetes, one-third present with severe periodontal disease and adult patients with severe periodontitis had increased risk of poor glycemic control, increasing the risk of oral and systemic complications. The discovery of common markers in chronic inflammatory human diseases would serve as potential targets for the development of novel therapeutics.
|Herrera, Bruno S; Hasturk, Hatice; Kantarci, Alpdogan et al. (2015) Impact of resolvin E1 on murine neutrophil phagocytosis in type 2 diabetes. Infect Immun 83:792-801|
|Freire, Marcelo O; Van Dyke, Thomas E (2013) Natural resolution of inflammation. Periodontol 2000 63:149-64|