Obesity Inhibits Innate Lung Bactericidal Functions

肥胖会抑制肺部先天杀菌功能

• 批准号: 10462029
• 负责人: Gabrielle Entrup
• 金额: $ 3.91万
• 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/10462029
• 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 system; Impairment; Infection; Inflammation; Inflammatory; Insulin Resistance; Kinetics; Knowledge; Lead; Link; Lung; 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; Production; Pseudomonas aeruginosa; Pseudomonas aeruginosa infection; Pseudomonas aeruginosa pneumonia; Public Health; Publishing; Regulation; Respiratory Tract Infections; Risk; Scientist; Signal Transduction; Site; Skin Tissue; Spleen; Stroke; Symptoms; TLR4 gene; Testing; Thinness; Tissues; Training; Transcription Alteration; 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; macrophage; 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。全球 39% 的人口超重，13% 的人口超重 人口肥胖。肥胖会导致许多其他疾病，例如心脏病、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， 到 2050 年，这一数字预计将增长到 6 亿多人。尽管 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，并且表现出更高的负担 疾病。尽管肥胖动物的骨髓细胞产量有所增加，但我们实验室之前的工作 研究表明，糖尿病伤口无法愈合与前列腺素 E2 (PGE2) 水平升高有关 募集到伤口的炎症巨噬细胞。此外，我们实验室过去的研究表明 证明 PGE2 信号传导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受到呼吸道铜绿假单胞菌的影响 PA01 菌株感染是由于肺驻留和招募的巨噬细胞功能受损所致。初步研究 证明肥胖糖尿病小鼠在 24 小时后肺部的铜绿假单胞菌负担确实增加 感染。此外，我们还确定，幼稚肥胖糖尿病小鼠的肺中性粒细胞有所增加 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 与瘦小鼠相比。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，中性粒细胞功能测定表明，来自肥胖糖尿病小鼠的中性粒细胞在杀伤细胞方面存在缺陷。 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的假设 不仅在先天免疫细胞募集方面存在缺陷，而且在免疫过程中也存在先天免疫细胞功能缺陷。 细菌性肺炎。该假设将通过两个具体目标进行检验： 目标 1) 确定函数 铜绿假单胞菌感染期间肺泡巨噬细胞的缺陷和目标 2) 决定细菌清除率 以及铜绿假单胞菌感染期间中性粒细胞募集缺陷。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，男性因肥胖引起的炎症更严重。 这些目标的实验将通过使用小鼠饮食诱导的肥胖模型、细胞衍生来完成 来自这些小鼠的细胞，以及来自患有和不患有 T2D 患者废弃血液样本的人类细胞。 这些创新研究的结果可能会为改善细菌性肺炎的治疗结果提供信息 T2D 患者。完成该提案还将使申请人能够接受严格的培训 实验设计、实施和解释将帮助她成为一名成功、独立的人 科学家。