Crosstalk Between T Cells and Airway Smooth Muscle in Obesity-Related Asthma

肥胖相关哮喘中 T 细胞和气道平滑肌之间的串扰

• 批准号: 10092500
• 负责人: Deepa Rastogi
• 金额: $ 5.7万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092500
• 关键词: Crosstalk; Between; Cells; Airway; Smooth

ABSTRACT Obese asthmatics have higher disease burden and worse pulmonary function, but are poorly responsive to current asthma medications, as compared to normal-weight children with asthma. This high disease burden with no effective medications highlights an urgent need for development of novel therapies for obesity-related asthma. Development of novel therapies is directly linked to elucidation of the pathobiology of obesity-related asthma. We and others have found evidence of systemic non-atopic TH cell inflammation in obese asthmatic children that correlates with pulmonary function deficits specific to obesity-related asthma. Using an RNA-Seq- based unbiased probe into the immunobiology of the non-atopic TH cell responses, we identified upregulation of several genes (DOCK5, VAV2, CDC42EP4, PAK3, MLK3, and PLD1) in the CDC42 pathway in obese asthmatic TH cells relative to normal-weight asthmatic TH cells. CDC42EP4 and DOCK5 gene expression correlated with lower airway obstruction only in obese asthmatic children. Based on the key role that CDC42 plays in T cell migration, adhesion, activation, and differentiation of naïve TH cells into TH1 and TH17 subsets, our results support a novel role for the CDC42 pathway in non-atopic immune responses in obesity-related asthma. Since TH cell adhesion to the airway smooth muscle (ASM) causes ASM activation, in light of our pilot findings of greater cytosolic calcium release in obese ASM in response to carbachol, a muscarinic agent, compared to normal-weight ASM, we hypothesize that CDC42 mediated increased migration and adhesion of obese asthmatic TH cells to ASM causes activation of muscarinic pathways in the ASM; this CDC42 mediated crosstalk between TH cells and ASM underlies the association of systemic non- atopic immune response with pulmonary function deficits in obesity-related asthma. We will utilize well- characterized ASM cells from obese and normal-weight individuals from Dr. Panettieri's lab and TH cells from extensively phenotyped obese and normal-weight urban minority asthmatic children collected during my K23 award to study the following aims. In Aim 1, we will test the hypothesis that CDC42 activation increases migration and adhesion of obese asthmatic TH cells to ASM cells. In Aim 2, we will determine if the obese asthmatic TH cell adhesion to ASM is a trigger event for ASM activation leading to activation of muscarinic pathways. Evidence of crosstalk between CDC42-mediated TH cell responses and ASM activation is of utmost clinical relevance since it links systemic non-atopic immune responses with airway physiology in obese asthma. This evidence will support future investigation of CDC42 pathway to identify proteins downstream of CDC42 that underlie non-atopic inflammation that impacts pulmonary function. We also expect to identify pathways in ASM as therapeutic targets for obesity-related asthma, a disease entity for which there are currently no effective treatments.

抽象的 肥胖的哮喘患者患有较高的疾病伯嫩，肺功能较差，但对 与正常体重儿童哮喘相比，目前的哮喘药物。这种高疾病伯恩 没有有效的药物强调迫切需要开发与肥胖有关的新疗法 哮喘。新疗法的发展与肥胖相关病理生物学的阐明直接相关 哮喘。我们和其他人发现肥胖哮喘中系统性非原子TH细胞注射的证据 与肺功能相关的儿童定义了与肥胖有关的哮喘的特异性。使用RNA-Seq- 基于对非原子TH细胞反应的免疫生物学的无偏探针，我们确定了上调 肥胖的Cdc42途径中的几种基因（Dock5，Vav2，cdc42ep4，pak3，mlk3和pld1） 相对于正常体重哮喘的TH细胞，哮喘的TH细胞。 cdc42ep4和dock5基因表达 仅在肥胖哮喘儿童中与较低的气道阻塞相关。基于CDC42的关键作用 在T细胞迁移，广告，激活和幼稚的TH细胞中的作用中， 我们的结果支持Cdc42途径在肥胖相关的非原子免疫反应中的新作用 哮喘。由于细胞对气道平滑肌（ASM）的粘附会导致ASM激活，因此鉴于我们的飞行员 肥胖ASM中较大的胞质钙释放的发现，响应于毒蕈碱剂卡巴乔尔（Carbachol） 与正常重量ASM相比，我们假设Cdc42介导的迁移增加和 肥胖哮喘细胞对ASM的粘附会导致ASM中毒蕈碱途径的激活； 这种Cdc42介导的TH细胞和ASM之间的串扰是全身性非 - 具有肺功能的特应免疫反应定义了与肥胖相关的哮喘。我们将利用 表征来自Panettieri博士实验室和TH细胞的肥胖和正常体重个体的ASM细胞 在我的K23期间收集的广泛表型肥胖和正常的城市少数哮喘儿童 奖励以下目标。在AIM 1中，我们将测试Cdc42激活增加的假设 肥胖的哮喘细胞迁移和遵守ASM细胞。在AIM 2中，我们将确定是否肥胖 哮喘对ASM的细胞粘附是ASM激活的触发事件，导致毒蕈碱激活 途径。 CDC42介导的TH细胞反应和ASM激活之间串扰的证据是最大的 临床相关性，因为它将系统性的非原子免疫复杂与肥胖哮喘中的气道生理联系起来。 该证据将支持CDC42途径的未来投资，以鉴定Cdc42下游的蛋白质 这是影响肺功能的非原子注射。我们还期望确定 ASM作为与肥胖相关哮喘的治疗靶标，目前没有的疾病实体 有效的治疗方法。