Obesity Inhibits Innate Lung Bactericidal Functions

肥胖会抑制肺部先天杀菌功能

• 批准号: 10708761
• 负责人: Gabrielle Entrup
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708761
• 关键词: 2019-nCoV; Adipose tissue; Adult; Affect; Alveolar Macrophages; Animals; Anti-Bacterial Agents; Antibacterial Response; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological; Biological Assay; Blood; Blood specimen; Bone Marrow; Cell physiology; Cells; Chronic; Clinical; Complication; Data; Defect; Diabetes Mellitus; Diabetic mouse; Diagnosis; Dinoprostone; Disease; Exhibits; Experimental Designs; Failure; Female; Gene Expression; Generations; Goals; Health; Heart Diseases; Hematopoietic; Host Defense; Hour; Human; Immune; Immune response; Immune signaling; Immune system; Impairment; Infection; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Knowledge; Link; Lung; Macrophage; Malignant Neoplasms; Measures; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; Neutrophil Infiltration; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Organ; Overweight; Patient-Focused Outcomes; Patients; Persons; Phagocytes; Phagocytosis; Population; Predisposition; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Public Health; Publishing; Regulation; Respiratory Tract Infections; Risk; Scientist; Sepsis; Signal Transduction; Site; Skin Tissue; Spleen; Stroke; Symptoms; TLR4 gene; Testing; Thinness; Tissues; Training; Transcription Alteration; Virus; Virus Diseases; Work; bactericide; burden of illness; chemokine; cytokine; diabetic; diabetic wound healing; diet-induced obesity; differential expression; experimental study; functional disability; immunoregulation; improved; improved outcome; innate immune function; innovation; insight; lung histology; male; microbial; mortality; neutrophil; novel; obese patients; oxidative damage; pulmonary function; recruit; respiratory; sex; soft tissue; stem; transcriptome sequencing; wound

Project Abstract Obesity is a major global public health concern. Worldwide, 39% of the population is overweight and 13% of the population is obese. Obesity contributes to many other diseases, such as heart disease, stroke, some cancers, and notably, type 2 diabetes (T2D). Currently, 425 million people globally have been diagnosed with T2D and this number is expected to grow to over 600 million people by 2050. Although T2D itself is a non-communicable disease, many patients with diabetes are more susceptible to microbial infections and exhibit a higher burden of disease. Although obese animals have an increased production of myeloid cells, previous work from our labs has shown that a failure to heal diabetic wounds corresponds to elevated levels of prostaglandin E2 (PGE2) in the inflammatory macrophages that are recruited to the wound. Furthermore, past studies from our lab have demonstrated that PGE2 signaling can impair the innate immune functions of macrophages. Therefore, we hypothesized that diabetic obese mice would be more susceptible to a respiratory Pseudomonas aeruginosa strain PA01 infection due to impaired function of lung resident and recruited macrophages. Preliminary studies demonstrate that obese diabetic mice do have an increased P. aeruginosa burden in the lung 24 hours after infection. Additionally, we have determined that naïve obese diabetic mice have an increase in lung neutrophils compared to lean mice, however, after infection with P. aeruginosa, these mice have a decrease in neutrophils compared to lean mice. This suggests that obese mice have a defect in neutrophil recruitment during infection. Additionally, neutrophil function assays show that neutrophils from obese diabetic mice have a defect in killing P. aeruginosa. These observations drive this proposal which will test the hypothesis that obese diabetic mice have not only a defect in innate immune cell recruitment, but also a defect in innate immune cell function during bacterial pneumonia. This hypothesis will be tested through two specific aims: Aim 1) determine the functional defects in alveolar macrophages during P. aeruginosa infection and Aim 2) determine the bacterial clearance and recruitment defects in neutrophils during P. aeruginosa infection. Throughout these aims, we explore sex as a biological variable, as males have enhanced obesity-induced inflammation compared to females. Experiments for these aims will be completed with the use of a murine diet induced obesity model, cells derived from these mice, and human cells derived from discarded blood samples from patients with and without T2D. The results from these innovative studies may inform treatments to improve outcomes from bacterial pneumonia in patients with T2D. Completion of this proposal will also allow for the applicant to receive rigorous training in experimental design, implementation, and interpretation that will help her become a successful, independent scientist.

项目摘要 肥胖是全球主要的公共卫生问题。在全球范围内，人口的39％超重，占13％ 人口肥胖。肥胖会导致许多其他疾病，例如心脏病，中风，一些取消者， 值得注意的是，2型糖尿病（T2D）。目前，全球有4.25亿人被诊断出患有T2D和 到2050年，这个数字预计将增长到超过6亿人。尽管T2D本身是不可传播的 疾病，许多糖尿病患者更容易受到微生物感染的影响，并且表现出更高的负担 疾病。尽管肥胖动物的产生增加了髓样细胞，但我们实验室的先前工作 已经表明，未能治愈糖尿病伤口对应于前列腺素E2（PGE2）的水平升高 招募到伤口的炎症巨噬细胞。此外，我们实验室的过去研究有 证明PGE2信号传导会损害巨噬细胞的先天免疫功能。因此，我们 假设糖尿病肥胖小鼠更容易受到呼吸道假单胞菌的影响 菌株PA01感染由于肺部居民和招募巨噬细胞功能受损而引起的。初步研究 证明肥胖的糖尿病小鼠在24小时后的肺中确实增加了铜绿假单胞菌伯嫩 感染。此外，我们已经确定幼稚的肥胖糖尿病小鼠的肺嗜中性粒细胞增加 然而，与瘦小小鼠相比，在铜绿假单胞菌感染后，这些小鼠的中性粒细胞降低 与瘦小鼠相比。这表明肥胖小鼠在感染期间嗜中性粒细胞募集缺陷。 此外，嗜中性粒细胞功能分析表明，来自肥胖糖尿病小鼠的中性粒细胞在杀死方面存在缺陷 P.铜绿。这些观察结果推动了这一建议，该提议将检验肥胖的糖尿病小鼠的假设 不仅具有先天免疫物招募的缺陷，而且还具有先天免疫功能的缺陷 细菌性肺炎。该假设将通过两个特定目的进行检验：目标1）确定功能 铜绿假单胞菌感染期间肺泡巨噬细胞的缺陷和目标2）确定细菌清除率 以及铜绿假单胞菌感染期间中性粒细胞中的缺陷。通过这些目标，我们探索性 作为一种生物学变量，与女性相比，男性具有增强的肥胖引起的感染。 这些目标的实验将通过使用鼠饮食诱导肥胖模型的细胞来完成 来自这些小鼠，以及来自有或没有T2D患者的丢弃血液样本的人类细胞。 这些创新研究的结果可能会为治疗方法提供信息，以改善细菌肺炎的预后 T2D患者。该提案的完成还将允许申请人接受严格的培训 实验设计，实施和解释，这将帮助她成为成功，独立的 科学家。