Obesity is a global problem affecting over 1 billion adults and 17.6 million children under 5 years of age. Since 1980, 3-fold increases in obesity have been reported worldwide. Obesity poses an increased risk of developing many secondary conditions, including atherosclerosis, diabetes, non-alcoholic fatty liver disease, periodontal disease, certain cancers, and asthma. Given the disease burden associated with obesity, a better understanding of the local and systemic complications arising from this condition and effective modalities for its treatment seem critical and timely. Obesity is now viewed to result in a dysregulation of the innate immune system leading to an attenuated systemic inflammation. However, a precise understanding of the molecular mechanisms that underlie this immune-metabolic linkage is lacking, but will be critically important for rational intervention. Intriguingly, and cogent to this proposal, recent epidemiological studies have linked obesity to periodontal disease. The possible causal relationship(s) between obesity and periodontitis, and the underlying biological mechanisms warrant a robust investigation. Provocatively, our preliminary data show that when wild-type mice are fed a high fat diet for 16 weeks - as a model for induced obesity they display a dramatic and reproducibly attenuated proinflammatory cytokine profile in a Porphyromonas gingivalis (P.g)-dependent model of periodontal disease, in contrast to lean mice fed a standard chow diet. Furthermore, in this model, obese animals experience greater periodontal bone loss compared to lean ones. Finally, we have found that obesity impairs the mechanisms associated with host clearance of P.g. from the oral environment. Based on these data, and data presented in this proposal, we hypothesize that diet-induced obesity (DIO) alters the innate immune response to P.g, such that macrophages mount an attenuated anti-bacterial response, which leads to aggravated periodontal bone loss. A better understanding of the link between obesity and innate immune response will likely have profound implications for the design of new therapies and modalities aimed at reducing clinical sequelae associated with obesity. In this application, we propose the following Specific Aims:
Aim 1 will determine the effect of DIO on the severity of P.g-associated experimental periodontitis.
Aim 2 will establish the functional significance of chromatin modification and TLR signaling pathways uniquely affected by DIO in response to P.g infection.
Aim 3 will determine the effect of TLR2 deficiency on DIO in our murine periodontitis model. Our approach should provide novel and crucial data that will deepen our understanding of the pathway-specific mechanisms involved in the diet-induced regulation of host innate immune response to pathogens. The characterization of diet-specific pathways may eventually allow the design of new classes of compounds to treat obesity-related diseases. NARRATIVE: Our approach will test the hypothesis that diet-induced obesity alters the immune response to Porphyromonas gingivalis which leads to an aggravated alveolar bone loss in obese animals. The results of these studies should provide novel and crucial data that will deepen our understanding of the pathway-specific mechanisms involved in the diet- induced regulation of host innate immune response to pathogens. New knowledge gained from the proposed studies will likely have profound implications for the design of new therapies and modalities aimed at reducing clinical sequelae associated with obesity.
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