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: 9789926
• 负责人: Deepa Rastogi
• 金额: $ 3.15万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789926
• 关键词: Actins; Adhesions; Asthma; Bronchodilator Agents; Calcium; Carbachol; Cell Adhesion; Cell Cycle; Cell model; Cells; Child; Childhood Asthma; Chronic Disease; Complement; Confocal Microscopy; Cytoskeleton; Development; Disease; Donor person; Emergency department visit; Event; Flow Cytometry; Foundations; Future; Gene Expression; Genes; Histamine; Hospitalization; Human; Immune response; Immunobiology; Individual; Inflammation; Inhalation; Interferon Type II; Interleukin-6; Investigation; Light; Link; Lung Transplantation; Measures; Mediating; Mentored Patient-Oriented Research Career Development Award; Methodology; Minority; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinics; Obesity; Pathway interactions; Pharmaceutical Preparations; Phenotype; Physiology; Play; Proteins; Pulmonary Function Test/Forced Expiratory Volume 1; Research; Research Design; Research Proposals; Role; Small Interfering RNA; Smooth Muscle Myocytes; Speed; Steroids; T-Lymphocyte; TNF gene; Testing; Th2 Cells; Therapeutic; Up-Regulation; VAV2 gene; Weight; airway obstruction; asthmatic; attenuation; base; burden of illness; career; cell motility; cellular development; clinically relevant; cytokine; effective therapy; migration; new therapeutic target; novel; novel therapeutics; peripheral blood; public health relevance; pulmonary function; recruit; respiratory smooth muscle; response; skills; therapeutic target; transcriptome sequencing

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 肥胖哮喘患者的疾病负担较高，肺功能较差，但对哮喘的反应较差 与正常体重的哮喘儿童相比，目前的哮喘药物治疗。这种高疾病负担 由于没有有效的药物，迫切需要开发治疗肥胖相关的新疗法 哮喘。新疗法的开发与肥胖相关病理学的阐明直接相关 哮喘。我们和其他人发现了肥胖哮喘患者全身性非特应性 TH 细胞炎症的证据 与肥胖相关哮喘特有的肺功能缺陷相关的儿童。使用 RNA-Seq- 基于对非特应性 TH 细胞反应的免疫生物学的无偏见探索，我们发现了上调 肥胖中 CDC42 通路中的多个基因（DOCK5、VAV2、CDC42EP4、PAK3、MLK3 和 PLD1） 哮喘 TH 细胞相对于正常体重的哮喘 TH 细胞。 CDC42EP4和DOCK5基因表达 仅与肥胖哮喘儿童的下气道阻塞相关。基于 CDC42 的关键作用 参与 T 细胞迁移、粘附、激活以及幼稚 TH 细胞分化为 TH1 和 TH17 亚群， 我们的结果支持 CDC42 通路在肥胖相关非特应性免疫反应中的新作用 哮喘。由于 TH 细胞粘附到气道平滑肌 (ASM) 会导致 ASM 激活，根据我们的试点 肥胖 ASM 中对卡巴胆碱（一种毒蕈碱剂）的反应导致胞质钙释放量增加， 与正常体重的 ASM 相比，我们假设 CDC42 介导了迁移和迁移的增加 肥胖哮喘 TH 细胞与 ASM 的粘附导致 ASM 中毒蕈碱途径的激活； 这种 CDC42 介导的 TH 细胞和 ASM 之间的串扰是系统性非 肥胖相关哮喘中特应性免疫反应与肺功能缺陷。我们将充分利用—— Panettieri 博士的实验室对来自肥胖和正常体重个体的 ASM 细胞以及来自 我的 K23 期间收集的广泛表型肥胖和正常体重的城市少数民族哮喘儿童 奖励研究以下目标。在目标 1 中，我们将测试 CDC42 激活增加的假设 肥胖哮喘 TH 细胞向 ASM 细胞的迁移和粘附。在目标 2 中，我们将确定肥胖者是否 哮喘 TH 细胞粘附 ASM 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重要的 临床相关性，因为它将全身非特应性免疫反应与肥胖哮喘的气道生理学联系起来。 该证据将支持未来对 CDC42 通路的研究，以识别 CDC42 下游的蛋白质 这是影响肺功能的非特应性炎症的基础。我们还希望找到以下途径： ASM 作为肥胖相关哮喘的治疗靶标，这是一种目前尚无治疗方法的疾病实体 有效的治疗。