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%的人口超重 人口是肥胖的。肥胖导致许多其他疾病，如心脏病、中风、一些癌症、 值得注意的是，2型糖尿病(T2D)。目前，全球已有4.25亿人被诊断出患有T2D和 预计到2050年，这一数字将增长到6亿以上。尽管T2D本身是一种非传染性 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。虽然肥胖动物的髓系细胞产量增加，但我们实验室之前的工作 研究表明，糖尿病创面愈合失败与前列腺素E2(PGE2)水平升高相对应 被招募到伤口的炎性巨噬细胞。此外，我们实验室过去的研究已经 证实PGE2信号可以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感染呼吸道铜绿假单胞菌 PA01株因肺内滞留和募集巨噬细胞功能受损而感染。初步研究 证明肥胖糖尿病小鼠24小时后肺部铜绿假单胞菌负荷增加 感染。此外，我们已经确定，单纯肥胖的糖尿病小鼠肺内中性粒细胞增加。 然而，与瘦小的小鼠相比，感染铜绿假单胞菌后，这些小鼠的中性粒细胞减少。 与瘦小的老鼠相比。这表明肥胖小鼠在感染过程中中性粒细胞募集存在缺陷。 此外，中性粒细胞功能分析表明，肥胖糖尿病小鼠的中性粒细胞在杀伤方面存在缺陷。 铜绿假单胞菌。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目标进行检验：目标1)确定功能 肺泡巨噬细胞在铜绿假单胞菌感染中的缺陷和目的2)决定细菌的清除 中性粒细胞在铜绿假单胞菌感染中的募集缺陷。在这些目标中，我们探索性 作为一个生物学变量，因为与女性相比，男性会加剧肥胖引发的炎症。 这些目标的实验将通过使用小鼠饮食诱导肥胖模型来完成，细胞来源 来自这些小鼠的，以及来自患有和不患有T2D的患者的废弃血液样本的人类细胞。 这些创新性研究的结果可能有助于改善细菌性肺炎的治疗结果。 在患有T2D的患者中。完成这项建议还将使申请人能够接受严格的培训 试验性的设计、实施和解释将帮助她成为一个成功的、独立的 科学家。