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The long-term goal of this study is to develop mode of treatment for inflammation in the oral cavity. To this end, we sought to investigate both (1) the mechanism regulating the integrity of the mucosal barrier, as well as (2) the epigenetic mechanisms by which inflammatory response is elicited and regulated. Epithelial tissue serves as an important barrier against infection. In response to physical injury or infection, this tissue undergoes significant phenotypic changes for eliciting its barrier function. For example, epithelial cells, major components of epithelial tissue, upregulate the expression of TGF- when the tissue is encountered by inflammation or injury in the human oral cavity. TGF- induces cellular proliferation and differentiation, and also initiates a reversible process known as epithelial-mesenchymal transition (EMT) for wound healing processes. During EMT, epithelial cells exhibit phenotypic changes, loss of cell-cell adhesion, enhanced migratory capacity, and disruption of epithelial integrity. We have demonstrated that transcription factors Grainyhead-like 2 (GRHL2) and p63 regulate epithelial proliferation and differentiation, and may regulate EMT in human keratinocytes. Thus, to explore the molecular mechanism of TGF- -dependent EMT, we investigated the effects of p63 and Grainyhead-like 2 (GRHL2) modulation on epithelial plasticity. We found that TGF- leads to downregulation of GRHL2 and p63 expression, and facilitation of EMT molecular phenotype. Knockdown of all p63 isoforms by transfection of p63 Si-RNA was sufficient to induce EMT phenotype in normal human keratinocytes (NHK), and EMT in NHK accompanied loss of GHRL2 and miR-200 family gene expression, both of which play crucial roles in determining epithelial phenotype. Modulation of GRHL2 in NHK also led to congruent changes in p63 expression. Lastly, conditional knockout of GRHL2 resulted in significant phenotypic changes affecting the epithelial barrier and led to enhanced Porphyromonas gingvalis (P.g.) bacterial load within the bloodstream. These findings indicate that GRHL2 and p63 play an important role in inhibiting TGF- -dependent EMT in epithelial cells, and that loss of GRHL2 expression induces phenotypic changes altering epithelial barrier function and facilitates accumulation of P.g. bacteria in the bloodstream. These bacteria are known to release lipoglycan endotoxin lipopolysaccharide (LPS) that triggers the expression of pro-inflammatory cytokines. Although previous literature has identified an association between dynamic demethylation of distinct histone marks and cytokine transcriptional activation, the role of histone lysine demethylases in the epigenetic regulation of inflammatory response is not well understood. Thus, to explore the epigenetic regulation of P.g. lipopolysaccharide (P.g. LPS) induced inflammatory response, we discovered a novel histone lysine demethylase KDM3C that regulates pro-inflammatory cytokine induction and inflammatory response. We found that P.g. LPS culture led to KDM3C upregulation and enrichment on the promoter regions of several inflammatory cytokines, driving their transcriptional activation by demethylating H3K9me2. Overexpression of histone methyltransferase G9a maintained the H3K9me2 repressive mark and prevented inflammatory cytokine induction. Knockout of KDM3C also prevented induction of inflammatory signaling molecules, including pro-inflammatory cytokines, by P.g. LPS. These findings indicate that KDM3C plays an important functional role in the epigenetic regulation of inflammatory response. Collectively, these data demonstrate the effect that injury or infection in the oral cavity can have on epithelial integrity and resistance against pathogenic bacteria, and the epigenetic mechanisms that trigger the inflammatory response to these bacteria. As a result, we have identified the potential of KDM3C as novel anti-inflammatory therapeutic target, and our understanding of the mechanisms regulating epithelial barrier function and inflammatory response will be useful in the management and treatment of inflammatory diseases affecting oral tissues.
Cellular and Molecular Mechanisms of Inflammation: Signal Transduction in Inflammatory Cells, Part A is a collection of papers that discusses the mechanisms of the transduction of signals linking stimulated receptors and cellular function. This book describes the pathways of signal transduction involved in stimulating functions of inflammatory cells connected with host defense and development of inflammatory injury. One paper notes the potential of using fluorescence methodology in analyzing ligand-receptor interactions in living systems during the natural abundance of cell surface receptors. Another paper discusses the structure and function of GTP-binding proteins in neutrophil signal transduction, particularly the role of oligomeric G proteins in signal transduction. One concern in signal transduction research is the physiological significance of the presence of multiple forms of proteins that can have identical functions. One paper reviews phosphatidylcholine breakdown and hormone action in the rat liver, focusing on G proteins and on inositol phospholipid breakdown. This book also discusses calcium translocation in signal transduction, as well as, a novel signal transduction pathway involving phosphatidylinositol 3-kinase. This book can prove beneficial for biochemists, micro-biologists, cellular researchers, and academicians involved in the study of cellular biology, physiology or oncology.
Receptors of Inflammatory Cells: Structure-Function Relationships is the first in a new serial on Cellular and Molecular Mechanisms of Inflammation. The purpose of this serial is to bring together the latest knowledge in various areas of research in this actively developing field around a topical focus. These volumes are not intended to present comprehensive reviews. Rather, each contribution is meant to be a status report from laboratories actively working in an area. This volume presents an analysis of the structure-function relationships of receptors. It is clear that the structure of receptors provides the initial guidance for numerous functions of each cell in the organism. Through an analysis of the submolecular features of the receptors that are responsible for the initiation of activity of diverse biochemical pathways within the cells, a molecular understanding of the all important initial, guiding events of cell functions will emerge. In the broad sense of cells involved in inflammation, this includes mitogenesis, gene transcription, generation of lipid metabolites and oxidants, clearance of molecules from the surrounding medium, and release of granular constituents from cytoplasmic vesicles into the external medium, among others. The contents of this first volume will serve as a foundation for the subject of the second volume, which is signal transduction. Four additional volumes are in preparation, including Endothelial Leukocyte-Adhesion Molecules, Leukocyte Adhesive Mechanisms in Inflammation and Immunity, a second volume on Signal Transduction, and Stimulation of Inflammatory Cells.
Advances in Stem Cells and Their Niches addresses stem cells during development, homeostasis, and disease/injury of the respective organs, presenting new developments in the field, including new data on disease and clinical applications. Video content illustrates such areas as protocols, transplantation techniques, and work with mice. Explores not only reviews of research, but also shares methods, protocols, and transplantation techniques Contains video content to illustrate such areas as protocols, transplantation techniques, and work with mice Each volume concentrates on one organ, making this a unique publication
New updated edition first published with Cambridge University Press. This new edition includes 29 chapters on topics as diverse as pathophysiology of atherosclerosis, vascular haemodynamics, haemostasis, thrombophilia and post-amputation pain syndromes.