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Principal Investigator: Apollo Stacy
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2024
Award: $249,000
Funding agency: National Institute of Dental and Craniofacial Research
Project Summary/Abstract
Research: Periodontitis (gum disease) is one of the most common inflammatory diseases worldwide,
affecting nearly 50% of adults (65 million people) in the US alone. Untreated, it can destroy the tissues that
support the teeth, eventually resulting in tooth loss. The cause of periodontitis is linked to the outgrowth of
multiple, rather than individual, pathogens in the oral microbiota. For instance, co-detection of Aggregatibacter
actinomycetemcomitans (Aa) with Filifactor alocis is a much greater predictor of future tissue destruction than
detection of Aa alone. However, how Aa and F. alocis interact to elicit pathology while evading host immunity
remains poorly understood. Microbiota-host interactions are often mediated by microbial metabolites, and a
major metabolite of F. alocis is hydrogen sulfide, a toxic gas highly enriched in periodontitis. Based on my
preliminary data, I hypothesize that F. alocis-derived sulfide triggers an immunological cascade that drives tissue
destruction while constructing a niche for Aa to proliferate via sulfide-resistant anaerobic respiration. Of note,
inexpensive, non-toxic drugs already exist that selectively inhibit anaerobic respiration (tungstate) or sequester
sulfide (bismuth). To test my hypothesis and the therapeutic value of these drugs, I will dissect how F. alocis-
derived sulfide impacts Aa (Aim 1) and the oral immune system (Aim 2) in complementary mouse models: thigh
abscess, which allows for precise control over composition of the infecting community, and ligature-induced
periodontitis, which allows for the assessment of oral immune responses. Through these Aims, I will potentially
establish innovative therapies targeted against microbiota-host interactions that promote periodontal disease.
Career Goals: My overarching goal as an independent investigator is to integrate the fields of oral
microbiology and immunology as a strategy to gain novel insight into the etiology of periodontitis. To achieve this
goal, I require additional training and knowledge in oral immunology as well as professional development in skills
essential for leading a successful laboratory. Career Development Plan and Environment: My mentor Y.
Belkaid, a renowned expert in microbiota-host interactions, is an investigator in the NIH Intramural Research
Program, one of the largest research centers in the world. In this unique environment, I will directly benefit from
the numerous resources in place to support my research project and career development, including microbiome
and immunology core facilities, frequent seminars and opportunities to engage colleagues/mentors, and regular
workshops on grant-writing, mentoring, and laboratory management. Furthermore, I have assembled a
mentoring team who will complement my expertise in Aa and the abscess model by closely overseeing my
training in the ligature model (NIDCR-based co-mentor N. Moutsopoulos) and F. alocis (collaborators R. Lamont
and H. Fletcher) as well as my transition to independence. By the end of my training plan, I will be well-positioned
to launch a productive independent career at the intersection of oral microbiology and immunology.
Terms: <21+ years old><A actinomycetemcomitans><A. actinomycetemcomitans><Abscess><Actinobacillus actinomycetemcomitans><Adult><Adult Human><Aerobic><Aerobic Bacteria><Affect><Aggregatibacter actinomycetemcomitans><Alveolar Bone Loss><Alveolar Resorption><Anaerobic Bacteria><Antibodies><Assay><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bacterium actinomycetem comitans><Bacterium comitans><Bioassay><Biological Assay><Bismuth><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Causality><Cell Respiration><Cellular Respiration><Chronic Periodontitis><Communities><Complement><Complement Proteins><Core Facility><Cysteine><Data><Detection><Development><Development Plans><Disease><Disorder><Drugs><Educational workshop><Environment><Etiology><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formulation><Future><Gases><Generalized Growth><Genetic><Goals><Grant><Growth><HPGF><Half-Cystine><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><Hydrogen Sulfide><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune response><Immune system><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><In Vitro><Individual><Inflammatory><Innovative Therapy><Interleukin-6><Interleukins><Intramural Program><Intramural Research Program><Investigators><Knowledge><L-Cysteine><Laboratories><Ligature><Link><Literature><MGI-2><Marrow Neutrophil><Mediating><Medication><Mentors><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Myeloid Differentiation-Inducing Protein><NIDCR><NIDR><NIH><National Institute of Dental Research><National Institute of Dental and Craniofacial Research><National Institutes of Health><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Oral><Oral Microbiology><Oxidants><Oxidizing Agents><Parodontosis><Pathology><Periodontal Bone Loss><Periodontal Diseases><Periodontal Resorption><Periodontitis><Persons><Pharmaceutical Preparations><Plasmacytoma Growth Factor><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Position><Positioning Attribute><Production><Productivity><Proliferating><R-Series Research Projects><R01 Mechanism><R01 Program><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Resources><Researchers><Resistance><Resources><Respiration><Risk><Role><Sulfides><Supervision><T-Cells><T-Lymphocyte><Testing><Therapeutic><Thigh><Thigh structure><Tissue Growth><Tissues><Tooth><Tooth Loss><Tooth structure><Training><United States National Institutes of Health><Workshop><Writing><adulthood><aerobe><aerobic metabolism><aerobic respiration><alveolar bone><alveolar supporting bone><anaerobe><anti-microbial><antimicrobial><bacterial genetics><bone loss><career><career development><causation><co-infection><coinfection><complementation><cytokine><developmental><disease causation><drug/agent><dysbacteriosis><dysbiosis><dysbiotic><electron acceptor><fitness><flow cytophotometry><global health><host microbiota><host microflora><host response><human disease><immune system response><immunopathology><immunoresponse><in vivo><insight><interferon beta 2><maxilla alveolar process><microbial><microbial imbalance><microbiome><mouse model><murine model><mutant><neutrophil><novel><ontogeny><oral immunology><oral microbial community><oral microbiota><oral microflora><oral pathogen><oxidative metabolism><pathogen><periodontal disorder><periodontium disease><periodontium disorder><resident microbes><resident microflora><resistant><respiratory mechanism><response><skills><social role><socket wall><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><teeth><thymus derived lymphocyte><translational therapeutics><translational therapy>