Obesity, Metabolic Syndrome and Asthma

肥胖、代谢综合征和哮喘

• 批准号: 9913853
• 负责人: Senad Divanovic
• 金额: $ 23.85万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-20 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913853
• 关键词: Adipose tissue; Affect; Age; Allergens; Antigens; Asthma; Atherosclerosis; Body Weight; C57BL/6 Mouse; Cardiovascular Diseases; Caring; Characteristics; Chronic; Clinical; Complex; Consensus; Data; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Exhibits; Experimental Models; Extrinsic asthma; Female; Gender; Glucose; Hepatic Tissue; High Fat Diet; Homeostasis; House mice; Housing; Human; Immune response; Immune system; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Response; Inhalation; Interleukin-1; Interleukin-17; Interleukin-6; Lead; Link; Lung; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Mild obesity; Minor; Modality; Modeling; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Onset of illness; Organ; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytes; Phenotype; Play; Population; Predisposition; Prevalence; Production; Public Health; Publishing; Refractory; Regulatory T-Lymphocyte; Reproducibility; Role; Severities; Severity of illness; Steroid therapy; Steroids; System; TNF gene; Temperature; Therapeutic; Time; Treatment Efficacy; Weight Gain; Woman; Work; asthma exacerbation; asthma model; asthmatic; biological adaptation to stress; biological sex; cohort; cytokine; disorder subtype; environmental allergen; feeding; granulocyte; improved; inflammatory lung disease; male; mouse model; neutrophil; new therapeutic target; non-alcoholic fatty liver disease; novel; novel therapeutic intervention; pandemic disease; recruit; response; sex; uptake

Allergic asthma, a disease that affects over 300 million people worldwide, is typically driven by Th2-dominated immune responses to environmental antigens. Obesity, a disorder afflicting 500 million people worldwide, is associated with chronic inflammation, elevated proinflammatory cytokine production, and metabolic dysfunction leading to the development of diabetes, cardiovascular disease, non-alcoholic fatty liver disease and various cancers. Recent evidence suggests the existence of several asthma “endotypes”– disease subtypes driven by unique underlying pathogenic mechanisms. The “obese asthma” endotype is associated with: (1) a shift away from Th2-dominated inflammation towards a more proinflammatory phenotype; (2) a reduction in therapeutic efficacy of steroids; and (3) a clear female bias in prevalence. While there is consensus regarding these clinical parameters, identification of underlying mechanisms of “obese asthma” has been hampered by the absence of a combined model of severe obesity and asthma in female mice. Although reproducible modeling of asthma is achieved in both male and female mice, modeling of obesity and metabolic dysfunction is largely limited to male mice. This is largely in part due to poor tractability of obesity and metabolic dysfunction in female mice. Our novel data demonstrate that housing female mice in temperatures close to their thermoneutral zone (the temperature at which they are in metabolic homeostasis – 30-33°C) with concomitant HFD feeding promotes development of severe obesity, adiposity and metabolic dysfunction comparable to that observed in male mice. Thus, we are now able to simultaneously assess the influence of obesity, adiposity, metabolic dysfunction, and sex on asthma pathogenesis. In this application, our two independent, yet related, Specific Aims seek to validate the ability of our novel model to recapitulate three frequent observations in obese asthmatics: (1) the shift towards a proinflammatory profile; (2) reduced efficacy of steroids; and (3) female preponderance. Specific Aim 1: Determine if severely obese female mice with metabolic dysfunction develop asthma comparable to the “obese asthma” endotype described in obese women. Using HFD- or control chow diet-fed male and female mice, housed at either standard (22°C) or thermoneutral (30-33°C) conditions, we will induce experimental asthma in a model of robust obesity and metabolic dysfunction. Features of experimental asthma will be correlated with weight gain, adiposity, parameters of metabolic dysfunction, in a sex-dependent manner. Specific Aim 2: Determine if obesity and metabolic dysfunction associate with development of steroid refractory asthma in female mice. The ability of inhaled and systemic steroids to inhibit experimental asthma and metabolic dysfunction will be assessed in HDM-challenged, HFD- or control diet-fed, TS- and TN- housed male and female mice. A better understanding of the pathogenesis of the “obese asthma” endotype will revolutionize care of obese asthmatics and allow for discovery of novel therapeutic approaches benefiting a large proportion of those underserved by current therapeutic modalities.

过敏性哮喘是一种影响全球3亿多人的疾病，通常由Th 2主导的 对环境抗原的免疫反应。肥胖是一种困扰全球5亿人的疾病， 与慢性炎症、促炎细胞因子产生升高和代谢功能障碍相关 导致糖尿病、心血管疾病、非酒精性脂肪肝和各种 癌的最近的证据表明存在几种哮喘“内在型”--由哮喘基因驱动的疾病亚型。 独特的潜在致病机制。“肥胖性哮喘”内型与：（1）远离 从Th 2主导的炎症向更促炎表型转变;（2）治疗性炎症减少， 类固醇的疗效;（3）患病率明显偏向女性。虽然对这些临床 参数，“肥胖性哮喘”的潜在机制的鉴定受到缺乏 雌性小鼠严重肥胖和哮喘的联合模型。虽然哮喘的可重复建模是 在雄性和雌性小鼠中实现，肥胖和代谢功能障碍的建模在很大程度上限于 雄性老鼠这在很大程度上是由于雌性小鼠的肥胖和代谢功能障碍的可处理性差。 我们的新数据表明，将雌性小鼠置于接近其热中性区的温度下（ 它们处于代谢体内平衡的温度-30-33 °C）与伴随的HFD进食促进 严重肥胖、肥胖症和代谢功能障碍的发展与雄性小鼠中观察到的相当。 因此，我们现在能够同时评估肥胖、肥胖症、代谢功能障碍和 性别对哮喘发病机制的影响。在本申请中，我们的两个独立但相关的具体目标旨在 验证了我们的新模型的能力，以概括肥胖哮喘患者的三个常见观察结果：（1） 向促炎性特征转变;（2）类固醇疗效降低;（3）女性优势。 具体目标1：确定患有代谢功能障碍的严重肥胖雌性小鼠是否发生哮喘 与肥胖妇女中描述的“肥胖性哮喘”内型相当。使用HFD或对照饲料 饲养在标准（22°C）或热中性（30-33°C）条件下的雄性和雌性小鼠，我们将 在健壮肥胖和代谢功能障碍模型中诱导实验性哮喘。实验特点 哮喘将与体重增加、肥胖、代谢功能障碍参数相关， 方式具体目标2：确定肥胖和代谢功能障碍是否与以下疾病的发生相关： 雌鼠类固醇难治性哮喘。吸入性和全身性类固醇抑制实验性 哮喘和代谢功能障碍将在HDM激发、HFD或对照饮食喂养、TS和TN- 饲养雄性和雌性小鼠。更好地了解“肥胖性哮喘”的发病机制， 彻底改变肥胖哮喘患者的护理，并允许发现新的治疗方法， 很大一部分人没有得到当前治疗方式的充分服务。