Role of Obesity in Infection

描述（由申请人提供）：肥胖是一个全球性问题，影响着超过10亿成年人和1760万5岁以下儿童。自1980年以来，全世界肥胖人数增加了3倍。肥胖会增加患许多继发性疾病的风险，包括动脉粥样硬化、糖尿病、非酒精性脂肪性肝病、牙周病、某些癌症和哮喘。考虑到与肥胖相关的疾病负担，更好地了解由肥胖引起的局部和全身并发症以及有效的治疗方式似乎至关重要和及时。肥胖现在被认为是先天免疫系统失调的结果，导致全身炎症减轻。然而，缺乏对这种免疫-代谢联系的分子机制的精确理解，但对合理干预至关重要。有趣的是，最近的流行病学研究将肥胖与牙周病联系起来。肥胖和牙周炎之间可能的因果关系以及潜在的生物学机制需要进行强有力的调查。令人兴奋的是，我们的初步数据显示，当野生型小鼠被喂食高脂肪饮食16周-作为诱导肥胖的模型-它们在牙龈卟啉单胞菌（P.g）依赖的牙周病模型中显示出显著且可重复的炎症细胞因子谱，与喂食标准食物的瘦小鼠相比。此外，在这个模型中，肥胖的动物比瘦的动物牙周骨质流失更严重。最后，我们发现肥胖损害了宿主从口腔环境中清除P.g.的相关机制。基于这些数据和本研究提出的数据，我们假设饮食诱导的肥胖（DIO）改变了先天免疫对pg的反应，使巨噬细胞产生减弱的抗菌反应，从而导致牙周骨质流失加剧。更好地了解肥胖和先天免疫反应之间的联系，可能会对设计旨在减少肥胖相关临床后遗症的新疗法和模式产生深远的影响。在这个应用中，我们提出以下具体目的：目的1将确定DIO对p.g.相关的实验性牙周炎的严重程度的影响。目的2将确定受DIO影响的染色质修饰和TLR信号通路在P.g感染应答中的功能意义。目的3将确定TLR2缺乏对小鼠牙周炎模型DIO的影响。我们的方法应该提供新的和重要的数据，这将加深我们对饮食诱导的宿主对病原体的先天免疫反应调节的途径特异性机制的理解。对饮食特异性途径的描述可能最终允许设计新型化合物来治疗肥胖相关疾病。

DESCRIPTION (provided by applicant): 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.