Inflammation is essential for effective control of infection;however, in chronic infectious diseases such as periodontal disease (PD), the resulting inflammation fails to adequately protect the host. The bacterium most associated with chronic generalized PD is Porphyromonas gingivalis. PD lesions are identified by loss of periodontal attachment, oral bone loss, significant influx of mononuclear cells, and expression of inflammatory markers at sites of disease. Expression of these pro-inflammatory molecules is controlled in part via innate immune pattern recognition receptors including the toll-like receptors (TLR). In vitro studies support roles for TLR signaling pathways regulate inflammation in response to P. gingivalis;however, these pathways are poorly defined. Therefore, a more detailed understanding of the host factors that regulate inflammation in response to P. gingivalis in the context of bone remodeling is needed. In addition to the local inflammatory lesions of the oral cavity associated with P. gingivalis infection, recent clinical and animal model data support a role for infection by organisms such as P. gingivalis and others including Chlamydophila pneumoniae with accelerated vascular plaque accumulation. Atherosclerosis is a complex inflammatory disease. Regulation of inflammation is thought to be key to preventing this disease. The nuclear hormone receptor liver X receptor (LXR) plays a key role in regulating expression of genes involved in cellular cholesterol efflux. Recently, a second function for LXR, namely regulation of TLRdependent inflammatory pathways has been identified. As innate immune signaling via TLRs is implicated in atherosclerosis, PD, and host response to P. gingivalis, and LXR is a regulator of TLR mediated inflammation, we speculated that LXR could influences both oral bone loss and atherosclerosis elicited by P. gingivalis. Here we propose an interrelated set of aims to test the hypothesis that LXR regulates inflammatory gene expression and bone loss elicited by P. gingivalis;moreover, LXR plays a central role in infection-accelerated chronic inflammatory vascular plaque accumulation. These studies will provide a detailed understanding of the role played by LXR in regulating inflammation that accompanies P. gingivalis infection.

Public Health Relevance

Porphyromonas gingivalis is associated with the oral chronic inflammatory diseases periodontal disease and the vascular inflammatory disease atherosclerosis. The nuclear hormone receptor liver X receptor (LXR) is a transcriptional regulator of genes involved in cholesterol mobilization, inflammation, and host response to infection. Bases on these known activities of LXR and our preliminary data, we will define the role of LXR in inflammation, oral bone loss, and atherosclerosis elicited by P. gingivalis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Boston University
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