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 肥胖哮喘患者的疾病负担较高，肺功能较差，但对 与患有哮喘的正常体重儿童相比，目前的哮喘药物。这种沉重的疾病负担 由于没有有效的药物治疗，迫切需要开发与肥胖相关的新疗法 哮喘。新疗法的发展直接与阐明肥胖相关的病理生物学有关 哮喘。我们和其他人发现肥胖哮喘患者存在全身性非特应性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序列- 基于对非特应性TH细胞反应的免疫生物学无偏见的探索，我们确定了上调 肥胖患者CDC42途径中几个基因(DOCK5、VAV2、CDC42EP4、PAK3、MLK3和PLD1)的研究 哮喘TH细胞相对正常体重哮喘TH细胞。CDC42EP4和DOCK5基因表达 仅在肥胖哮喘儿童中与下呼吸道阻塞相关。基于CDC42的关键作用 在T细胞迁移、黏附、激活和分化为TH1和TH17亚群方面发挥作用， 我们的结果支持了CDC42通路在肥胖相关的非特应性免疫反应中的新作用 哮喘。根据我们的飞行员的说法，由于TH细胞与呼吸道平滑肌(ASM)的黏附导致ASM激活 发现肥胖性ASM在卡巴胆碱作用下细胞内钙释放增加。 与正常体重的ASM相比，我们假设CDC42介导了更多的迁移和 肥胖性哮喘TH细胞与ASM的黏附导致ASM中M胆碱途径的激活； 这种CDC42介导的TH细胞和ASM之间的串扰是系统性非... 肥胖相关性哮喘患者的特应性免疫反应与肺功能缺陷。我们会好好利用- 来自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 获奖研究以下目标。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细胞的迁移和黏附。在目标2中，我们将确定肥胖者 哮喘TH细胞与ASM的黏附是ASM激活的触发事件，导致M 小路。CDC42介导的TH细胞反应和ASM激活之间存在串扰的证据是最明显的 临床相关性，因为它将肥胖性哮喘的全身非特应性免疫反应与呼吸道生理联系起来。 这一证据将支持未来对cdc42途径的研究，以确定cdc42下游的蛋白质。 这是影响肺功能的非特应性炎症的基础。我们还希望确定在 ASM作为肥胖相关哮喘的治疗靶点，这是一种目前还没有治疗的疾病实体 有效的治疗方法。