CAUSE Clinical Research Center New York (CAUSE-CRC)

项目概要/摘要 小儿哮喘对生活在城市社区的儿童造成不成比例的影响，部分原因是环境因素 接触过敏原、压力和空气污染。本项目设立临床研究中心，开展 网络范围内和特定地点的临床研究和试验，最终目标是开发有效的哮喘 适用于居住在低收入城市环境中的儿童的治疗或预防方法。对于一个重要的 大量哮喘患者，指南指导的治疗并不能实现疾病控制，这表明需要， 针对这些患者的表型进行个性化治疗的潜在益处。显而易见的是 通过对成人和儿童的聚类分析，有一组严重哮喘患者的特征较少 2 型炎症以及 2 型细胞因子靶向生物制剂可能效果较差。儿童居住在 内城区暴露于过敏原，尤其是蟑螂，并对过敏原敏感，引发 2 型炎症 反应并暴露于高水平的室内和室外刺激物和污染物中，这些刺激物和污染物可能会引发 TH1 和 TH17 中性粒细胞炎症。需要更好地了解非特应性的机制 哮喘。以 IL-6 作为生物标志物的全身炎症被认为是介导哮喘的一种机制 严重程度。 IL-6由免疫系统细胞产生并由气道上皮细胞分泌，已被 被提议作为哮喘治疗的潜在目标。而细胞因子和可溶性受体水平以及遗传 IL-6R 的研究已与哮喘相关，即受体在体内发出信号的内在能力 不同表型群体却没有。本研究的目的是确定内在信号传导是否 蟑螂阴性、特应性较低的儿童和 蟑螂过敏、特应性较高的儿童患有中度至重度哮喘。我们假设这一点以及 IL-6 受体信号传导与发病率的关系。我们假设遗传多态性会改变 内在的 IL-6 信号传导，并且 IL-6 信号传导将是发病率的决定因素。该协议将测试探索性 假设污染和压力会导致那些具有较高内在信号传导的人病情恶化。 为了检验这一假设，我们提出了一项旨在识别儿童内在 IL-6 信号传导差异的研究 患有哮喘。该研究将包括以下儿童： 1) 年龄在 6 至 20 岁之间； 2）有历史 反复发作的喘息/持续性哮喘至少一年； 3) 居住在低收入人口普查区 美国市中心社区。内在 IL-6 信号传导和 SNP 携带者状态的研究将在外周血上进行 基线时的血液单核细胞 (PBMC)。这些研究将针对鼻上皮细胞的一个子集进行 的参与者。我们建议每 3 个月进行一次为期 12 个月的随访，以前瞻性地确定 IL-6 信号传导与症状和恶化的关系。

Project Summary/Abstract Pediatric asthma disproportionately impacts children who live in urban communities partly due to environmental exposure to allergens, stress and air pollution. This project establishes a Clinical Research Center to conduct both network-wide and site-specific clinical studies and trials with the ultimate goal of developing effective asthma treatment or prevention approaches applicable to children residing in low-income urban settings. For a significant number of asthma patients, guideline-directed treatment does not achieve disease control, suggesting the need, and potential benefit, for treatment(s) that are personalized to the phenotype of these patients. As evident by cluster analyses in adults and children, there is a group of severe asthmatics that have fewer characteristics of type 2 inflammation and in whom type 2 cytokine-targeting biologics may be less effective. Children living in inner-cities are exposed and sensitized to allergens, particularly cockroach, triggering type 2 inflammatory response and exposed to high levels of indoor and outdoor irritants and pollutants which can trigger TH1 and TH17 neutrophilic inflammation. There is a need to have a better understanding of mechanisms of non-atopic asthma. Systemic inflammation with IL-6 as a biomarker is a mechanism that is postulated to mediate asthma severity. IL-6 is produced by cells of the immune system and secreted by airway epithelial cells and has been proposed as a potential target for asthma therapy. While cytokine and soluble receptor levels, as well as genetic studies of IL-6R have been examined in relation to asthma, the intrinsic capacity for the receptor to signal within differing phenotypic populations has not. The objective of this study is to determine whether intrinsic signaling responses to circulating IL6 and other cytokines differs between cockroach negative, lower atopic children and cockroach allergic, higher atopic children with moderate to severe asthma. We hypothesize that and the relationship of IL-6 receptor signaling to morbidity. We hypothesize that genetic polymorphisms will modify intrinsic IL-6 signaling and that IL-6 signaling will be a determinant of morbidity. The protocol will test exploratory hypotheses that pollution and stress lead to exacerbations in those with higher intrinsic signaling. To test this hypothesis, we propose a study designed to identify differences in intrinsic IL-6 signaling in children with asthma. The study will include children who: 1) are between the ages of 6 and 20 years; 2) have a history of recurrent wheeze / persistent asthma of at least one year duration; and 3) live in low-income census tracts of U.S. inner-city communities. Studies of intrinsic IL-6 signaling and SNP carrier status will be done on peripheral blood mononuclear cells (PBMC) at baseline. These studies will be done on nasal epithelial cells on a subset of participants. We propose a 12-month follow up at 3-month intervals to prospectively determine the relationship of IL-6 signaling to symptoms and exacerbations.