Role of Obesity in Infection

描述(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。据报道，自1980年以来，全球范围内肥胖人数增加了3倍。肥胖增加了发生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，更好地了解这种情况引起的局部和全身并发症以及有效的治疗方式似乎是至关重要和及时的。肥胖现在被认为会导致先天免疫系统的失调，从而导致全身炎症减轻。然而，缺乏对这种免疫-代谢联系背后的分子机制的精确理解，但对于合理的干预将是至关重要的。有趣的是，最近的流行病学研究将肥胖与牙周病联系起来，这对这一提议很有说服力。肥胖和牙周炎之间可能的因果关系(S)及其潜在的生物学机制值得进行强有力的调查。具有挑衅性的是，我们的初步数据显示，当野生型小鼠被喂以高脂饮食16周--作为诱导性肥胖的模型，它们在牙周病依赖的牙周疾病模型中表现出戏剧性的且可重复地减弱的促炎细胞因子谱，与喂养标准饮食的瘦小鼠形成对比。此外，在这个模型中，肥胖的动物比瘦的动物经历更多的牙周骨丢失。最后，我们发现肥胖损害了与宿主清除P.G.相关的机制。从口腔环境中。基于这些数据和本提案中提出的数据，我们假设饮食诱导的肥胖(DIO)改变了对P.G的先天免疫反应，使巨噬细胞产生减弱的抗菌反应，从而导致牙周骨丢失加重。更好地了解肥胖和先天免疫反应之间的联系，可能会对旨在减少肥胖相关临床后遗症的新疗法和方式的设计产生深远的影响。在这项应用中，我们提出了以下具体目标：目标1将确定DIO对P.G相关性实验性牙周炎严重程度的影响。目的2建立染色质修饰和TLR信号通路在P.G感染中受DIO独有影响的功能意义。目的3在我们的小鼠牙周炎模型中，确定TLR2缺乏对DIO的影响。我们的方法应该提供新的和关键的数据，将加深我们对饮食诱导的宿主对病原体的先天性免疫反应的调节所涉及的特定途径的机制的理解。特定饮食途径的特征可能最终允许设计新的化合物类别来治疗肥胖相关疾病。 叙述：我们的方法将检验这一假设，即饮食诱导的肥胖改变了对牙龈卟啉单胞菌的免疫反应，从而导致肥胖动物的牙槽骨严重丢失。这些研究的结果应该提供新的和关键的数据，将加深我们对饮食诱导宿主对病原体的天然免疫反应的调节所涉及的特定途径的机制的理解。从拟议的研究中获得的新知识可能会对旨在减少肥胖相关临床后遗症的新疗法和模式的设计产生深远的影响。

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.