ingest cdrApp 2018-08-23T17:53:51.114Z d39a25df-af15-48e9-aec2-c9af81a997a2 modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T17:54:32.773Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-08-23T17:54:44.402Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-08-23T17:55:07.768Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-08-23T17:55:30.671Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-27T15:46:16.008Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-21T16:50:15.703Z Lu Sun Author Oral and Craniofacial Biomedicine PhD Program School of Dentistry THE ROLE of MORN2 AND TRAF3IP2 GENETIC VARIANTS IN MODULATING INNATE IMMUNE RESPONSE TO PERIODONTAL PATHOGENS Periodontal disease is a polygenic disease that is associated with inflammatory response to the oral biofilm. Although it is believed that microbial pathogens are necessary to the causal pathway, a key factor to determine whether individuals will develop periodontitis is the way how the hosts respond to the microflora resides in their periodontium. Genetic polymorphisms that will cause a change in the encoded protein or its expression, which may alter host innate or adaptive immunity, such as host barrier function and inflammatory responses, to microorganism and determine susceptibility to inflammatory disease. Thus it is necessary to seek candidate genetic function to explain the differences in susceptibility to periodontal disease. Our recent genome-wide association study (GWAS) identified a missense single nucleotide polymorphism SNP (rs3099950) in the gene MORN2 that codes for a key membrane protein. We have also identified a missense SNP (rs13190932) in the gene TRAF3IP2 locus which is involved IL-17 signaling. These two genetic variants are associated with a P.gingivalis (P.g) dominant and A. actinomycetemcomitans (A.a) dominant periodontal disease subtypes. To date, only one study has described the function of MORN2 that serves as a macrophage protein that promotes the phagocytosis and killing of organisms via LC3-asscociated phagocytosis. TRAF3IP2 is involved in IL-17 signaling and mucosal immunity serving as an adaptor protein for the IL-17 receptor. However, the role of MORN2 and TRAF3IP2 in periodontal disease is unknown. In Chapter 1, the background of periodontal disease and how the SNPs were identified by GWAS were described. In Chapter 2, we investigated the role of MORN2 in modulating innate immune response to periodontal pathogens and our studies suggest that MORN2 plays a critical role in the LC3-associated phagocytosis – mediated killing of periodontal pathogen (P.g) as well as cytokine/chemokine response through Ca2+ flux and NF-kB activation. In Chapter 3, we explored the role of TRAF3IP2 mediated IL-17 pathway in periodontal disease. Our study suggests that TRAF3IP2 engaged homeostatic IL-17 pathway plays a protective role in a P.g induced alveolar bone loss and colonization through neutrophil recruitment, maintenance epithelial barrier and induction of antimicrobial peptides. Defective TRAF3IP2 shifts the oral commensal communities. Finally in Chapter 4, we discuss the significance and future study directions. In summary, these findings clarify the molecular mechanism of MORN2 and TRAF3IP2 function and provide insight into the genetic basis of MORN2 and TRAF3IP2 in periodontal disease susceptibility. Spring 2018 2018 Dentistry eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Steven Offenbacher Thesis advisor Steven Offenbacher Thesis advisor Toni Darville Thesis advisor Jennifer Webster-Cyriaque Thesis advisor Mitsuo Yamauchi Thesis advisor Sompop Bencharit Thesis advisor text Lu Sun Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry THE ROLE of MORN2 AND TRAF3IP2 GENETIC VARIANTS IN MODULATING INNATE IMMUNE RESPONSE TO PERIODONTAL PATHOGENS Periodontal disease is a polygenic disease that is associated with inflammatory response to the oral biofilm. Although it is believed that microbial pathogens are necessary to the causal pathway, a key factor to determine whether individuals will develop periodontitis is the way how the hosts respond to the microflora resides in their periodontium. Genetic polymorphisms that will cause a change in the encoded protein or its expression, which may alter host innate or adaptive immunity, such as host barrier function and inflammatory responses, to microorganism and determine susceptibility to inflammatory disease. Thus it is necessary to seek candidate genetic function to explain the differences in susceptibility to periodontal disease. Our recent genome-wide association study (GWAS) identified a missense single nucleotide polymorphism SNP (rs3099950) in the gene MORN2 that codes for a key membrane protein. We have also identified a missense SNP (rs13190932) in the gene TRAF3IP2 locus which is involved IL-17 signaling. These two genetic variants are associated with a P.gingivalis (P.g) dominant and A. actinomycetemcomitans (A.a) dominant periodontal disease subtypes. To date, only one study has described the function of MORN2 that serves as a macrophage protein that promotes the phagocytosis and killing of organisms via LC3-asscociated phagocytosis. TRAF3IP2 is involved in IL-17 signaling and mucosal immunity serving as an adaptor protein for the IL-17 receptor. However, the role of MORN2 and TRAF3IP2 in periodontal disease is unknown. In Chapter 1, the background of periodontal disease and how the SNPs were identified by GWAS were described. In Chapter 2, we investigated the role of MORN2 in modulating innate immune response to periodontal pathogens and our studies suggest that MORN2 plays a critical role in the LC3-associated phagocytosis – mediated killing of periodontal pathogen (P.g) as well as cytokine/chemokine response through Ca2+ flux and NF-kB activation. In Chapter 3, we explored the role of TRAF3IP2 mediated IL-17 pathway in periodontal disease. Our study suggests that TRAF3IP2 engaged homeostatic IL-17 pathway plays a protective role in a P.g induced alveolar bone loss and colonization through neutrophil recruitment, maintenance epithelial barrier and induction of antimicrobial peptides. Defective TRAF3IP2 shifts the oral commensal communities. Finally in Chapter 4, we discuss the significance and future study directions. In summary, these findings clarify the molecular mechanism of MORN2 and TRAF3IP2 function and provide insight into the genetic basis of MORN2 and TRAF3IP2 in periodontal disease susceptibility. Dentistry Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Steven Offenbacher Thesis advisor Steven Offenbacher Thesis advisor Toni Darville Thesis advisor Jennifer Webster-Cyriaque Thesis advisor Mitsuo Yamauchi Thesis advisor Sompop Bencharit Thesis advisor 2018 2018-05 eng text Lu Sun Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry Periodontal disease is a polygenic disease that is associated with inflammatory response to the oral biofilm. Although it is believed that microbial pathogens are necessary to the causal pathway, a key factor to determine whether individuals will develop periodontitis is the way how the hosts respond to the microflora resides in their periodontium. Genetic polymorphisms that will cause a change in the encoded protein or its expression, which may alter host innate or adaptive immunity, such as host barrier function and inflammatory responses, to microorganism and determine susceptibility to inflammatory disease. Thus it is necessary to seek candidate genetic function to explain the differences in susceptibility to periodontal disease. Our recent genome-wide association study (GWAS) identified a missense single nucleotide polymorphism SNP (rs3099950) in the gene MORN2 that codes for a key membrane protein. We have also identified a missense SNP (rs13190932) in the gene TRAF3IP2 locus which is involved IL-17 signaling. These two genetic variants are associated with a P.gingivalis (P.g) dominant and A. actinomycetemcomitans (A.a) dominant periodontal disease subtypes. To date, only one study has described the function of MORN2 that serves as a macrophage protein that promotes the phagocytosis and killing of organisms via LC3-asscociated phagocytosis. TRAF3IP2 is involved in IL-17 signaling and mucosal immunity serving as an adaptor protein for the IL-17 receptor. However, the role of MORN2 and TRAF3IP2 in periodontal disease is unknown. In Chapter 1, the background of periodontal disease and how the SNPs were identified by GWAS were described. In Chapter 2, we investigated the role of MORN2 in modulating innate immune response to periodontal pathogens and our studies suggest that MORN2 plays a critical role in the LC3-associated phagocytosis – mediated killing of periodontal pathogen (P.g) as well as cytokine/chemokine response through Ca2+ flux and NF-kB activation. In Chapter 3, we explored the role of TRAF3IP2 mediated IL-17 pathway in periodontal disease. Our study suggests that TRAF3IP2 engaged homeostatic IL-17 pathway plays a protective role in a P.g induced alveolar bone loss and colonization through neutrophil recruitment, maintenance epithelial barrier and induction of antimicrobial peptides. Defective TRAF3IP2 shifts the oral commensal communities. Finally in Chapter 4, we discuss the significance and future study directions. In summary, these findings clarify the molecular mechanism of MORN2 and TRAF3IP2 function and provide insight into the genetic basis of MORN2 and TRAF3IP2 in periodontal disease susceptibility. Dentistry Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Steven Offenbacher Thesis advisor Steven Offenbacher Thesis advisor Toni Darville Thesis advisor Jennifer Webster-Cyriaque Thesis advisor Mitsuo Yamauchi Thesis advisor Sompop Bencharit Thesis advisor 2018 2018-05 eng text Sun_unc_0153D_17958.pdf uuid:b300d0b1-a7c5-4e2b-9d75-8c57bf4ce7c4 2020-08-23T00:00:00 2018-06-20T15:53:04Z proquest application/pdf 3680682