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 肥胖是一个主要的全球公共卫生问题。在世界范围内，39%的人口超重，13%的人体重超标。 人口肥胖。肥胖导致许多其他疾病，如心脏病，中风，某些癌症， 尤其是2型糖尿病（T2D）。目前，全球有4.25亿人被诊断患有T2D， 预计到2050年，这一数字将增至6亿多人。虽然T2D本身是一种非传染性疾病， 疾病，许多糖尿病患者更容易受到微生物感染，并表现出更高的负担， 疾病尽管肥胖动物的骨髓细胞产量增加，但我们实验室之前的工作 已经表明，糖尿病伤口愈合失败对应于糖尿病患者体内前列腺素E2（PGE2）水平升高， 炎症性巨噬细胞聚集到伤口此外，我们实验室过去的研究 证明PGE2信号传导可以损害巨噬细胞的先天免疫功能。所以我们 假设糖尿病肥胖小鼠对呼吸道铜绿假单胞菌更敏感， 菌株PA01感染由于肺驻留和募集的巨噬细胞的功能受损。初步研究 结果表明，肥胖糖尿病小鼠在给药后24小时肺中的铜绿假单胞菌负荷确实增加， 感染此外，我们已经确定，幼稚肥胖糖尿病小鼠的肺中性粒细胞增加， 然而，与瘦小鼠相比，感染铜绿假单胞菌后，这些小鼠的中性粒细胞减少， 与瘦老鼠相比。这表明肥胖小鼠在感染期间中性粒细胞募集方面存在缺陷。 此外，中性粒细胞功能测定显示，来自肥胖糖尿病小鼠的中性粒细胞在杀伤 P.铜绿。这些观察结果推动了这一提议，该提议将检验肥胖糖尿病小鼠 不仅先天免疫细胞募集缺陷，而且先天免疫细胞功能缺陷， 细菌性肺炎这一假设将通过两个具体的目标进行测试：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，目的2）确定细菌清除 以及铜绿假单胞菌感染期间中性粒细胞的募集缺陷。通过这些目标，我们探索性 作为一个生物学变量，因为与女性相比，男性的肥胖引起的炎症增强。 用于这些目的的实验将使用鼠饮食诱导的肥胖模型完成，所述小鼠饮食诱导的肥胖模型中含有来源于小鼠的细胞。 来自这些小鼠，以及来自患有和不患有T2D的患者的废弃血液样品的人细胞。 这些创新研究的结果可能会为改善细菌性肺炎的治疗提供信息 在T2D患者中。完成此提案还将允许申请人接受严格的培训， 实验设计，实施和解释，这将有助于她成为一个成功的，独立的， 科学家