Role of Obesity in Infection

肥胖在感染中的作用

基本信息

批准号：
7525483
负责人：
Salomon Amar
金额：
$ 38.59万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7525483
关键词：
Address Adipocytes Adult Affect Age-Years Agonist Alveolar Bone Loss Animals Anti-Inflammatory Agents Anti-inflammatory Antibacterial Response Antibodies Apoptosis Area Asthma Atherosclerosis Attenuated Bacteria Biological Biological Assay Biopsy Blocking Antibodies Body Weight Body mass index Bone Tissue C57BL/6 Mouse Child Chromatin Chronic Class Clinical Communicable Diseases Complex Condition Connective Tissue DNA Binding Data Defect Diabetes Mellitus Diet Diet Modification Disease Progression Engineering Environment Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Exposure to Fatty acid glycerol esters Functional disorder Funding Gene Expression Genes Genetic Transcription Genomics Gingiva Harvest Hour Immune Immune response Immune system In Vitro Individual Infection Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Insulin Interleukin-10 Interleukin-6 Intervention Investigation Knowledge Laboratories Leptin Life Ligature Link Lipopolysaccharides Liver Liver diseases Malignant Neoplasms Measurement Measures Mediating Mediator of activation protein Messenger RNA Metabolic Metabolic Diseases Modality Modeling Modification Molecular Monoclonal Antibodies Mus Nonesterified Fatty Acids Nuclear Obese Mice Obesity Obesity associated disease Oral Overweight Pathway interactions Patients Periodontal Diseases Periodontitis Persons Placement Polymerase Chain Reaction Population Porphyromonas gingivalis Process Production Protein Overexpression Proteins Proteomics RNA Receptor Signaling Regulation Reporting Research Rest Risk Role Saturated Fatty Acids Serum Severities Signal Pathway Signal Transduction Signal Transduction Pathway Skeletal Muscle Standards of Weights and Measures TLR2 gene TLR4 gene TNF gene Testing Time Tissue Sample Tissues Toll-Like Receptor 2 Tooth structure Transfection Week Western Blotting Wild Type Mouse base bone loss burden of illness cytokine day design experience feeding fimbrillin in vivo loss of function macrophage microbial monocyte neutralizing antibody non-alcoholic fatty liver novel obesity treatment pathogen promoter remediation research study response stem transcription factor

项目摘要

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.

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。据报道，自 1980 年以来，全球肥胖人数增加了 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、非酒精性脂肪肝、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至关重要且及时。现在认为肥胖会导致先天免疫系统失调，从而导致全身炎症减弱。然而，对这种免疫代谢联系背后的分子机制的精确理解仍然缺乏，但这对于合理干预至关重要。有趣的是，最近的流行病学研究已将肥胖与牙周病联系起来，这一点也令人信服。肥胖和牙周炎之间可能存在的因果关系以及潜在的生物学机制需要进行强有力的研究。令人兴奋的是，我们的初步数据表明，当野生型小鼠被喂食高脂肪饮食 16 周时，作为诱发肥胖的模型，它们在牙龈卟啉单胞菌 (P.g) 依赖的牙周模型中表现出显着且可重复减弱的促炎细胞因子谱。疾病，与喂养标准饲料的瘦小鼠形成鲜明对比。此外，在该模型中，与瘦动物相比，肥胖动物的牙周骨质流失更大。最后，我们发现肥胖会损害与宿主清除 P.g. 相关的机制。来自口腔环境。根据这些数据以及本提案中提供的数据，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，使得巨噬细胞的抗菌反应减弱，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旨在减少与肥胖相关的临床后遗症的新疗法和模式的设计产生深远的影响。在本申请中，我们提出以下具体目标：目标 1 将确定 DIO 对 P.g 相关实验性牙周炎严重程度的影响。目标 2 将确定响应 P.g 感染的 DIO 独特影响的染色质修饰和 TLR 信号通路的功能意义。目标 3 将确定我们的小鼠牙周炎模型中 TLR2 缺陷对 DIO 的影响。我们的方法应该提供新颖且重要的数据，以加深我们对饮食诱导的宿主对病原体先天免疫反应的调节所涉及的途径特异性机制的理解。饮食特异性途径的表征最终可能允许设计新型化合物来治疗肥胖相关疾病。叙述：我们的方法将检验这样的假设：饮食引起的肥胖会改变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流失加剧。这些研究的结果应该提供新颖且重要的数据，从而加深我们对饮食诱导调节宿主对病原体先天免疫反应的途径特异性机制的理解。从拟议研究中获得的新知识可能会对旨在减少与肥胖相关的临床后遗症的新疗法和模式的设计产生深远的影响。