Chronic inflammation culminates in devastating events, results in significant host pathology, and is associated with a number of human diseases including autoimmune diseases, infectious diseases, neoplastic diseases, and inflammatory vascular plaque accumulation. The pathogenic bacteria Chlamydophila pneumoniae and Porphyromanas gingivalis induce a chronic inflammatory response, although how these pathogens induce and maintain chronic inflammation is not well defined. The central hypothesis of this P01 is that pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders. To test this hypothesis we propose the following Aims:
Aim 1. To define the signaling pathways by which inflammatory mediators are induced in response to P. gingivalis and C. pneumoniae in endothelial cells, macrophages, and platelets.
Aim 2. To define the contribution of transcription factors in inflammatory responses to P. gingivalis and C. pneumoniae.
Aim 3. To define how P. gingivalis and C. pneumoniae stimulation of inflammatory mediators via these pathways modulates endothelial cell, platelet and macrophage function.
Aim 4. To define the role of these signaling pathways in the pathogenesis of P. gingivalis and C. pneumoniae induced thrombosis and chronic inflammation in a mouse model. The following Projects propose detailed studies to address these Aims: Project 1-The Role of Innate Immunity and Pathogen-Induced Inflammation in Platelet Function;Project 2-Innate Immune Defenses Against Acute and Chronic Infection with C. pneumoniae. Project 3- Innate Immunity, Lipid Signaling, and Chronic Infection. &Project 4- Innate Immune Mechanisms Involved in P. gingivalis-Induced Chronic Inflammation. The following Cores will service these Projects: A. Administrative Core, B. In Vitro Core, and C. Animal Core. These collaborative and synergistic studies will define the role of specific innate immune signaling molecules in P. gingivalis and C. pneumoniae induced inflammatory responses in cells relevant to chronic inflammatory processes. Furthermore, using defined animal models of inflammation we will characterize the roles of these innate immune pathways in inflammatory processes in vivo. Enhanced understanding of the roles of specific innate immune signaling pathways, which participate in proinflammatory mediator expression and functional immune responses will provide a promising avenue for novel therapies for chronic inflammatory disorders. PROJECT 1: THE ROLE OF INNATE IMMUNITY AND PATHOGEN-INDUCED INFLAMMATION IN PLATELET FUNCTION (FREEDMAN, J) PROJECT 1 DESCRIPTION (provided by applicant): While there is evidence that chronic inflammation and infection promotes plaque formation, acute infections are associated with a transient five-fold increased risk of unstable coronary and vascular syndromes caused by platelet dependent thrombosis. While many strains of bacteria induce platelet aggregation, the mechanisms by which bacteria stimulate platelets has had minimal investigation. In preliminary data utilizing comprehensive microarray analyses, and a large community cohort of almost 2,000 subjects, we found distinct patterns of platelet gene expression in patients with cardiovascular disease. While several TLRs were detected in platelets, the expression of TLR2 and IL1R in particular were increased in patients with cardiovascular disease. Importantly, the functionality of TLR in platelets was established as incubation of platelets with TLR2 ligands dose-dependently induced platelet activation and aggregation. In addition, we found enhanced platelet function and platelet-monocyte/neutrophil binding with C. pneumoniae infection in vivo, and P. gingivalis incubation. The central hypothesis of the overall program project is that "Pathogen stimulation via innate immune recognition modulates inflammatory mediator regulation of host immune cell function resulting in chronic inflammatory disorders". The central hypothesis of Project 1 is that bacteria mediate pro-thrombotic and -inflammatory processes in platelets via innate immune pathways. To investigate this hypothesis, we propose the following Aims:
Aim 1. To define the role of TLR2 and IL-1R in C. pneumoniae and P. gingivalis enhanced platelet function.
Aim 2. To define C. pneumoniae and P. gingivalis mediated modulation of TLR2- and IL1R-dependent signaling pathways in platelets and NFkappaB-dependent transcription in megakaryocytes.
Aim 3. To define the role of TLR2 and IL-1 R in platelet specific responses to C. pneumoniae and P. gingivalis dependent thrombosis in vivo.

National Institute of Health (NIH)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Minnicozzi, Michael
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Boston University
Internal Medicine/Medicine
Schools of Medicine
United States
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Shaik-Dasthagirisaheb, Y B; Huang, N; Weinberg, E O et al. (2015) Aging and contribution of MyD88 and TRIF to expression of TLR pathway-associated genes following stimulation with Porphyromonas gingivalis. J Periodontal Res 50:89-102
Huang, Nasi; Gibson 3rd, Frank C (2014) Immuno-pathogenesis of Periodontal Disease: Current and Emerging Paradigms. Curr Oral Health Rep 1:124-132
Koupenova, Milka; Vitseva, Olga; MacKay, Christopher R et al. (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124:791-802
Shaik-Dasthagirisaheb, Yazdani B; Huang, Nasi; Gibson 3rd, Frank C (2014) Inflammatory response to Porphyromonas gingivalis partially requires interferon regulatory factor (IRF) 3. Innate Immun 20:312-9
Beaulieu, Lea M; Lin, Elaine; Mick, Eric et al. (2014) Interleukin 1 receptor 1 and interleukin 1? regulate megakaryocyte maturation, platelet activation, and transcript profile during inflammation in mice and humans. Arterioscler Thromb Vasc Biol 34:552-64
Clancy, Lauren; Freedman, Jane E (2014) New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer. J Thromb Thrombolysis 37:12-6
Freedman, Jane E (2014) Inherited dysfunctional nitric oxide signaling and the pathobiology of atherothrombotic disease. Circ Res 114:1372-3
He, Xianbao; Berland, Robert; Mekasha, Samrawit et al. (2013) The sst1 resistance locus regulates evasion of type I interferon signaling by Chlamydia pneumoniae as a disease tolerance mechanism. PLoS Pathog 9:e1003569
Freedman, Jane E; Tanriverdi, Kahraman (2013) Defining miRNA targets: balancing simplicity with complexity. Circulation 127:2075-7
Shaik-Dasthagirisaheb, Y B; Huang, N; Baer, M T et al. (2013) Role of MyD88-dependent and MyD88-independent signaling in Porphyromonas gingivalis-elicited macrophage foam cell formation. Mol Oral Microbiol 28:28-39

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