Oral infections associated with the gingival margin and subgingival sulcus lead to host inflammatory responses. Gingivitis is primarily a response to the bacteria in plaque. This "disease" affects nearly everyone in the population, at some time during their life. Periodontitis is a multifactorial disease that encompasses the hard and soft tissue, microbial colonization (with/without invasion), inflammatory responses, and adaptive immune responses. Periodontal inflammation and tissue destruction result from variations in the subgingival bacterial ecology that trigger deleterious host responses, with current evidence suggesting altered production and/or release of an array of destructive host mediators that lead to tissue destruction. However, recent studies have supported that certain putative oral pathogens produce a array of physiologic gene products (e.g. proteases) that have the capacity to engage and stimulate various host cell receptors resulting in a substantially enhanced synthesis of biomolecules that have been implicated in tissue destruction (e.g. IL-1ss, TNF1). Thus, while strategies of combating gingivitis are primarily designed to be managed by mechanical and/or nonspecific antimicrobial therapies to decrease the overall magnitude of bacterial challenge in the plaque; targeting periodontitis requires additional considerations relative to unique features of the microbial composition of the biofilms, and potentially critical host cell signaling mechanisms that may be unique to these pathogens. This STTR proposal is focusing on a strategy to identify natural plant-based agents that will inhibit proteases from significant oral pathogens, P. gingivalis, T. denticola, and T. forsythia. These proteases have been shown to relate to disease sites, in vitro growth and survival, production of inflammatory mediators, and in vivo virulence. Thus, interfering with the activity of these crucial molecules should provide an innovative new strategy to biologically interfere with infection and disease processes provoked by these oral pathogens. Gingivitis and periodontitis affect as large a proportion of the global population as any disease(s) known to mankind. Thus, identifying and developing more effective therapeutic regimens targeting aspects of the chronic infection and inflammation would provide a significant benefit to these individuals. Specific Aims are to document the effect of select natural products on the growth, host cell triggering, and virulence capacity of these bacteria.
Public Health Relevance: This STTR proposal aims to evaluate natural products for their ability to improve oral health by developing therapeutic treatments for gingival inflammation and tissue distruction. Specific Aims are to isolate and analyze natural products with anti-proteases properties to treat oral infections/diseases.
Public Health Relevance Statement: Principal Investigator/Program Director (Last, First, Middle): Huang, Chifu Brad PROJECT NARRATIVE This STTR proposal aims to evaluate natural products for their ability to improve oral health by developing therapeutic treatments for gingival inflammation and tissue distruction. Specific Aims are to isolate and analyze natural products with anti-proteases properties to treat oral infections/diseases. PHS 398/2590 (Rev. 09/04) Page 18 Continuation Format Page
Project Terms: Abscess; Acute; Adhesins, Bacterial; Affect; Alveolodental Ligament; Alveolodental Membrane; Anaerobic Bacteria; Anti-Infective Agents; Anti-Infective Drugs; Anti-Infectives; Anti-infective Preparation; AntiInfective Drugs; AntiInfectives; Antiinfective Agents; Antiproteases; Arginine; Arginine, L-Isomer; Bacteria; Bacteria, Anaerobic; Bacterial Adhesins; Bacteroides gingivalis; Biological; Biological Factors; Biological Function; Biological Process; Body Tissues; Buccal Cavity; Carya; Causality; Cavitas Oris; Cell Communication and Signaling; Cell Signaling; Cells; Characteristics; Chemicals; Chronic; Chronic Periodontitis; Clinical Trials; Clinical Trials, Unspecified; Complex; Connective Tissue; Cysteine Endopeptidases; Cysteine Protease; Cysteine Proteinases; Cytokines, Chemotactic; Defense Mechanisms; Degradation Pathway; Degradative Pathway; Detection; Disease; Disease by Site; Disorder; Disorder by Site; Dose; Ecology; Effectiveness; Endopeptidase Inhibitors; Endopeptidase-Activated Receptors; Environment; Environmental Science; Enzyme Antagonist; Enzyme Inhibitor; Enzyme Inhibitor Agent; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epithelial; Epithelial Cells; Esteroproteases; Etiology; Exhibits; Factor, Biologic; Forsythia; Frequencies (time pattern); Frequency; Generalized Growth; Genetic Alteration; Genetic Change; Genetic defect; Gingiva; Gingival; Gingivitis; Goals; Goldenbells; Grant; Growth; Halitosis; Head and Neck, Buccal Cavity; Hickory Tree; Homologous Chemotactic Cytokines; Host Defense Mechanism; Human; Human, General; INFLM; Immune response; In Situ; In Vitro; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Intercrines; Intermediary Metabolism; Intracellular Communication and Signaling; Kgp protease; L-Arginine; Lead; Lesion; Lian qiao; Libraries; Life; Link; Literature; Lys-gingipain; METBL; Mammals, Mice; Man (Taxonomy); Man, Modern; Mechanics; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Metabolic; Metabolic Processes; Metabolism; Mice; Microbe; Microbial Biofilms; Microorganisms, General; Modeling; Mouth; Murine; Mus; Mutation; Natural Products; Nutrient; Oral; Oral cavity; Oral health; Outcome; P. gingivalis; P.gingivalis; Paradentium; Paradentiums; Parodontosis; Pathogenicity; Pathway interactions; Pattern; Pb element; Pecans; Peptidase Inhibitors; Peptidases; Peptide Hydrolase Inhibitors; Peptide Hydrolases; Peptide Peptidohydrolase Inhibitors; Periodontal Diseases; Periodontal Infection; Periodontal Ligament; Periodontal Membrane; Periodontitis; Periodontium; Pharmaceutical Resources; Phase; Physiologic; Physiological; Physiology; Phytochemical; Plant Extracts; Plants; Plants, General; Population; Porphyromonas gingivalis; Principal Investigator; Process; Production; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protease Antagonists; Protease Inhibitor; Protease-Activated Receptors; Proteases; Proteinase Inhibitors; Proteinase-Activated Receptors; Proteinases; Proteins; Proteolytic Enzymes; Protocols, Treatment; RGM; Receptor Cell; Receptor Protein; Receptors, Proteinase-Activated; Regimen; Relative; Relative (related person); Reporting; Research; Role; SIS cytokines; STTR; Screening procedure; Signal Transduction; Signal Transduction Systems; Signaling; Site; Small Business Technology Transfer Research; Structure; T. denticola; T.denticola; Taxon; Testing; Therapeutic; Therapeutic Intervention; Thiol Protease; Time; Tissue Growth; Tissues; Tooth; Tooth Supporting Structures; Tooth structure; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treponema denticola; Variant; Variation; Virulence; Virulent; abstracting; adhesin; alveolar bone; alveolar bone of maxilla; alveolar process of maxilla; alveolar supporting bone; anaerobe; anti-microbial; antimicrobial; bactericidal; bactericide; bad breath; base; biofilm; biological signal transduction; chemoattractant cytokine; chemokine; chymotrypsin; clinical investigation; combat; commensal bacteria; commensal microbes; communicable disease control agent; cytokine; dental health; design; designing; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; enzyme activity; experiment; experimental research; experimental study; extracellular; gene product; genome mutation; gingipain; gingipain K; heavy metal Pb; heavy metal lead; host response; human disease; immunoresponse; improved; in vivo; infection mouth; inhibitor; inhibitor/antagonist; innovate; innovation; innovative; intervention therapy; lysine gingipain; microbial; microbial colonization; microorganism; mouse model; novel; ontogeny; oral biofilm; oral infection; oral infectious; oral malodor; oral pathogen; pathogen; pathway; periodontal disorder; periodontium disease; periodontium disorder; periodontopathogen; prevent; preventing; programs; proteinase T; psychological defense mechanism; rapid growth; receptor; research study; response; screening; screenings; social role; socket wall; soft tissue; teeth; tooth surface
