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).

项目概要 许多研究已经明确了肥胖如何损害慢性炎症。相比之下，人们知之甚少 肥胖如何损害体液免疫，体液免疫负责抗体的产生。建立底层 鉴于肥胖个体的增加，将肥胖与抗体产生受损联系起来的因素至关重要 对病毒/细菌感染的易感性以及对不同疫苗接种的反应较差。在分子水平上， 抗体的产生部分受到专门的促解决介质 (SPM) 的调节。 SPM 很有效 由二十二碳六烯酸 (DHA) 等多不饱和脂肪酸合成的免疫溶解剂。我们和 其他人发现，由 DHA 合成的 SPM 可以促进流感感染时抗体的产生，并且 疫苗接种。此外，DHA 衍生的 SPM 在肥胖症中缺乏，并且与肥胖相关 肥胖小鼠的亚油酸。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，我们的数据引导我们检验肥胖的中心假设 接种流感疫苗后不能有效产生抗体的受试者的循环能力下降 DHA 衍生的 SPM 水平和亚油酸水平增加。为了解决这个假设，我们将依靠 对大型临床研究中存储的血液样本进行分析，其中受试者被分层为反应者 （即产生抗体的瘦和肥胖个体）和无反应者（即产生抗体的瘦和肥胖受试者） 接种季节性三价灭活流感疫苗后未有效产生抗体）。方法 将依赖基于质谱的代谢脂组学分析、火焰离子化气相色谱法 检测和 ELISA。影响：该提案将建立受损抗体生产之间的关键联系 和人类水平的肥胖。这将为未来 SPM 的机理研究和调查奠定基础 和亚油酸作为人类潜在的可改变变量，以改善病毒反应的结果 感染/疫苗接种。该提案的完成将深入了解主要的公共卫生负担， 这是传染病（流感）与非传染性疾病（肥胖）的融合。