Role of Obesity in Infection

肥胖在感染中的作用

• 批准号: 7809374
• 负责人: Salomon Amar
• 金额: $ 45.48万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-23 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809374
• 关键词: 5 year old; Adult; Affect; Algorithms; Animal Model; Animals; Arts; Bacteria; Bacterial Infections; Biochemical Pathway; Bone Marrow; Candidate Disease Gene; Cations; Cells; Child; Clinical; Clinical Trials; Communicable Diseases; Complementary DNA; Computer Simulation; Data; Diet; Down-Regulation; Fatty acid glycerol esters; Funding; Gene Expression; Genes; Genetic; Genome; Human; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-10; Interleukin-6; Kinetics; Knowledge; Lead; Link; Maps; Metabolic; Metabolism; Modality; Modeling; Modification; Molecular; Mouse Cell Line; Mus; Mutation; Nutrient; Obesity; Parents; Pathway interactions; Periodontal Diseases; Play; Porphyromonas gingivalis; Positioning Attribute; Process; Psyche structure; Reaction; Recovery; Regulation; Retinal Cone; Role; Signal Pathway; Small Interfering RNA; TLR2 gene; TNF gene; Technology; Testing; Tissues; United States National Institutes of Health; Up-Regulation; Validation; cytokine; design; efficacy testing; feeding; graduate student; in vitro testing; interest; macrophage; mathematical model; metabolic abnormality assessment; mouse model; novel; nutrition; parent project; pathogen; programs; public health relevance; reconstruction; research study; response; text searching; tool

DESCRIPTION (provided by applicant): This is a competitive revision to the active parent application RO1 DE15989: "Role of Obesity in Infection" in response to Notice Number (NOT-OD-09-058) and Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. Obesity affects over 1 billion adults and 17.6 million children under 5 years of age. Obesity is known to result in a dysregulation of the innate immune response to infection. While the molecular mechanism that underlies this immune/inflammatory-metabolic linkage is not well understood recent studies have linked obesity to periodontal disease, a common infectious disease associated with the bacterium Porphyromonas gingivalis (P.g), and characterized by inflammation and destruction of periodontal tissues. Our own data shows that feeding mice a high fat diet induces defective proinflammatory cytokine response to P.g infection. In this two-year revision, we will extend the scope of the parent aims P- Aim 2b and P-Aim 2c and hire 2 more graduate students to accelerate the tempo of discovery . Specifically, we will identify a set of genes that are essential in the response to infection in mouse bone marrow macrophage (BMM) cells and will design modifications of these genes that will bring the response to infection of obese (OB) cells close to the response of lean (LN) cells. The response to infection will be quantified by the expression levels of five genes TNF, IL-6, iNOS, IL-10, and IL-1. According to the parent aim P-Aim 2b, we will focus on a specific TLR2 signaling pathway, which is thought to play a central role in the response to bacterial infection. The focus of the metabolic study will be on the effect of FFA, according to parent P-Aim 2c. We will test the efficiency of the design in vitro in murine BMM. This revision proposes therefore the following four specific aims: Aim 1: Construction of a mathematical model for the TLR2 gene network; Aim 2: Construction of a mouse BMM metabolic model; Aim 3: Design of genetic modifications affecting the response to infection in OB cells; Aim 4: In vitro testing of genetic modifications in mouse cell lines. The four specific aims listed above will lead to a significant increase in the scope of the overall project. By combining state-of-art computational approaches with experimental trials, we will be able to predict the cause of the phenotypic differences between the OB and LN cells, and try experimentally only genes that pass our in silico tests. This is in contrast with the initial scope of the parent aim P-Aim 2b, which was to identify genes that are differentially expressed and then directly test the effect of their perturbations experimentally. By including metabolic analysis, we will be able to better understand the effect of nutrition on the response to infection, and link nutrition to the gene expression response. In particular, we will quantify the effect of FFA, as initially proposed in the parent aim P-Aim 2c. At the end of this two-year revision, we will be in position of testing efficacy of our candidates in our periodontal animal model in hopes of moving to human clinical trials. PUBLIC HEALTH RELEVANCE: This competitive revision project will test the hypothesis that diet-induced obesity alters the immune response to Porphyromonas gingivalis in obese animals in response to Notice Number NOT-OD-09-058. The results of these 2 year supplement 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）：这是对主动父申请RO1 DE15989的竞争性修订：“肥胖在感染中的作用”，响应通知号（NOT-OD-09-058）和通知标题：NIH宣布竞争性修订申请的恢复法案资金可用性。肥胖影响着超过10亿成年人和1760万5岁以下儿童。众所周知，肥胖会导致先天免疫系统对感染的反应失调。虽然这种免疫/炎症-代谢联系的分子机制尚不清楚，但最近的研究已将肥胖与牙周病联系起来，牙周病是一种与牙龈卟啉单胞菌（P.g）有关的常见传染病，其特征是牙周组织的炎症和破坏。我们自己的数据表明，喂养小鼠高脂肪饮食诱导有缺陷的促炎细胞因子对P.g感染的反应。在这个为期两年的修订中，我们将扩大父目标P-Aim 2b和P-Aim 2c的范围，并聘请2名研究生来加快发现的速度。具体来说，我们将确定一组在小鼠骨髓巨噬细胞（BMM）感染反应中必不可少的基因，并将设计这些基因的修饰，使肥胖（OB）细胞对感染的反应接近瘦（LN）细胞的反应。对感染的反应将通过TNF、IL-6、iNOS、IL-10和IL-1这五个基因的表达水平来量化。根据母体目标P-Aim 2b，我们将专注于一个特定的TLR2信号通路，它被认为在对细菌感染的反应中起核心作用。根据母体P-Aim 2c，代谢研究的重点将放在FFA的作用上。我们将在小鼠BMM体外测试设计的效率。因此，本次修订提出以下四个具体目标：目标1：构建TLR2基因网络的数学模型；目的2：建立小鼠BMM代谢模型；目的3：设计影响OB细胞对感染反应的基因修饰；目的4：小鼠细胞系基因修饰的体外测试。上面列出的四个具体目标将导致整个项目范围的显著增加。通过将最先进的计算方法与实验试验相结合，我们将能够预测OB和LN细胞之间表型差异的原因，并在实验中只尝试通过我们的计算机测试的基因。这与母体目标P-Aim 2b的初始范围形成对比，该目标是鉴定差异表达的基因，然后直接通过实验测试其扰动的影响。通过代谢分析，我们将能够更好地了解营养对感染反应的影响，并将营养与基因表达反应联系起来。特别是，我们将量化FFA的影响，正如最初在母目标P-Aim 2c中提出的那样。在这两年的修订结束时，我们将在我们的牙周动物模型中测试我们的候选药物的功效，希望能进入人体临床试验。