SPMs, linoleic acid, and antibody levels in obesity

肥胖症中的 SPM、亚油酸和抗体水平

• 批准号: 10189019
• 负责人: SAAME R SHAIKH
• 金额: $ 7.48万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-28 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189019
• 关键词: Address; Age; Agreement; Anabolism; Antibodies; Antibody Formation; Antigens; Atherosclerosis; B-Lymphocytes; Bacterial Infections; Binding; Blood specimen; COVID-19 pandemic; Cardiovascular Diseases; Chronic; Clinical Research; Communicable Diseases; Data; Defect; Detection; Disease; Docosahexaenoic Acids; Drug usage; Enzyme-Linked Immunosorbent Assay; Enzymes; Fatty Acids; Fatty Liver; Flame Ionization; Future; Gas Chromatography; High Fat Diet; Human; Humoral Immunities; Impairment; Infection; Inflammation; Influenza; Influenza vaccination; Insulin Resistance; Investigation; Lead; Link; Linoleic Acids; Lipids; Literature; Mass Spectrum Analysis; Mediator of activation protein; Metabolic; Molecular; Mus; Natural Immunity; Non obese; Obese Mice; Obesity; Outcome; Parents; Plasma; Polyunsaturated Fatty Acids; Predisposition; Production; Public Health; Race; Research; Risk Factors; Smoking Status; Testing; Thinness; Time; Vaccination; Viral; Virus Diseases; adaptive immune response; adaptive immunity; base; improved outcome; in vivo; influenza infection; influenza virus vaccine; insight; murine antibody; novel therapeutic intervention; obese person; programs; responders and non-responders; response; sex; success; western diet

PROJECT SUMMARY Numerous studies have defined how obesity impairs chronic inflammation. In contrast, far less is known about how obesity impairs humoral immunity, which is responsible for antibody production. Establishing underlying factors that link obesity with impaired antibody production is critical given that obese individuals have increased susceptibility to viral/bacterial infections and poor responses to differing vaccinations. At a molecular level, antibody production is regulated, in part, by specialized pro-resolving mediators (SPMs). SPMs are potent immunoresolvants synthesized from polyunsaturated fatty acids such as docosahexaenoic acid (DHA). We and others have found that SPMs synthesized from DHA boost antibody production upon influenza infection and vaccination. Furthermore, DHA-derived SPMs are deficient in obesity and associated with an elevation in linoleic acid in obese mice. Linoleic acid is extremely abundant in the western diet and may be a major reason why SPMs are deficient in the obese. Collectively, our data lead us to test the central hypothesis that obese subjects that do not effectively produce antibodies upon influenza vaccination have decreased circulating levels of DHA-derived SPMs and increased levels of linoleic acid. To address this hypothesis, we will rely on analyses of blood samples stored from a large clinical study in which subjects were stratified as responders (i.e. lean and obese individuals that produced antibody) and non-responders (i.e. lean and obese subjects that did not effectively produce antibody) upon the seasonal trivalent inactivated influenza vaccine. The approach will rely on mass spectrometry based metabololipidomic analyses, gas chromatography with flame ionization detection, and ELISAs. Impact: This proposal will establish key links between impaired antibody production and obesity at the human level. This will set the basis for future mechanistic studies and investigation of SPMs and linoleic acid as potential modifiable variables in humans to improve outcomes in response to viral infections/vaccinations. Completion of this proposal will had provided insight into a major public health burden, which is the convergence of an infectious disease (influenza) with a noncommunicable disease (obesity).

项目摘要 许多研究已经确定了肥胖如何损害慢性炎症。相比之下， 肥胖如何损害负责抗体产生的体液免疫。建立基础 鉴于肥胖者的增加，肥胖与抗体产生受损之间的联系因素至关重要 对病毒/细菌感染的易感性和对不同疫苗接种的不良反应。在分子水平上， 抗体的产生部分地由专门的促分解介质（SPMs）调节。SPM是有效的 由多不饱和脂肪酸如二十二碳六烯酸（DHA）合成的免疫溶解剂。我们和 其他人已经发现由DHA合成的SPM在流感感染时促进抗体产生， 预防针此外，DHA衍生的SPM在肥胖症中是缺乏的，并且与肥胖症的升高相关。 肥胖小鼠体内的亚油酸。亚油酸在西方饮食中极其丰富，可能是一个主要原因 为什么肥胖者缺乏SPM总的来说，我们的数据使我们能够测试肥胖的核心假设， 在流感疫苗接种后不能有效产生抗体的受试者的循环减少 DHA衍生的SPM水平和亚油酸水平增加。为了解决这个假设，我们将依赖于 分析从一项大型临床研究中储存的血液样本，其中受试者被分层为应答者 (i.e.产生抗体的瘦和肥胖个体）和无应答者（即 不能有效地产生抗体）。的方法 将依赖于基于质谱的代谢脂质组学分析、气相色谱火焰离子化 检测和ELISA。影响：该提案将建立受损抗体产生之间的关键联系 和肥胖症。这将为今后的机理研究和SPM的调查奠定基础 和亚油酸作为人类潜在的可改变变量，以改善对病毒感染的反应结果。 感染/疫苗接种。这项提案的完成将使人们深入了解一个重大的公共卫生负担， 这是传染性疾病（流感）与非传染性疾病（肥胖）的融合。