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.

摘要 肥胖型哮喘患者的疾病负担更高，肺功能更差，但对 目前的哮喘药物，与正常体重的哮喘儿童相比。这种高疾病负担 没有有效的药物，突出了迫切需要开发新的治疗肥胖相关疾病的方法。 哮喘新疗法的开发与肥胖相关的病理生物学的阐明直接相关。 哮喘我们和其他人已经发现肥胖哮喘患者全身性非特应性TH细胞炎症的证据， 与肥胖相关哮喘的肺功能缺陷相关的儿童。使用RNA测序- 基于对非特应性TH细胞应答的免疫生物学的无偏探测，我们鉴定了 肥胖症患者CDC 42通路中的几个基因（DOCK 5、VAV 2、CDC 42 EP 4、PAK 3、MLK 3和PLD 1） 哮喘TH细胞相对于正常重量的哮喘TH细胞。CDC 42 EP 4和DOCK 5基因表达 仅在肥胖哮喘儿童中与下气道阻塞相关。基于CDC 42的关键作用， 在T细胞迁移、粘附、活化和幼稚TH细胞分化为TH 1和TH 17亚群中起作用， 我们的研究结果支持了CDC 42通路在肥胖相关的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）引起ASM激活，根据我们的试验， 在肥胖ASM中响应卡巴胆碱，一种毒蕈碱剂， 与正常体重的ASM相比，我们假设CDC 42介导的迁移增加， 肥胖哮喘TH细胞粘附于ASM引起ASM中毒蕈碱途径的激活; 这种CDC 42介导的TH细胞和ASM之间的串扰是全身性非- 肥胖相关哮喘患者肺功能缺陷的特应性免疫应答我们会好好利用- Panettieri博士实验室的肥胖和正常体重个体的ASM细胞和来自 在我的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，我们将检验CDC 42活化增加的假设。 肥胖哮喘TH细胞与ASM细胞的迁移和粘附。在目标2中，我们将确定 哮喘TH细胞粘附于ASM是ASM激活的触发事件，导致毒蕈碱受体活化， 途径。CDC 42介导的TH细胞反应和ASM激活之间串扰的证据是最充分的 临床相关性，因为它将全身非特应性免疫应答与肥胖性哮喘的气道生理学联系起来。 这一证据将支持未来对CDC 42通路的研究，以鉴定CDC 42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确定 ASM作为肥胖相关性哮喘的治疗靶点，目前还没有 有效的治疗。