CAUSE Clinical Research Center New York (CAUSE-CRC)

项目摘要/摘要 儿童哮喘对生活在城市社区的儿童的影响不成比例，部分原因是环境 暴露于过敏原、压力和空气污染。本项目成立临床研究中心进行 全网络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办法。对于一个重要的 哮喘患者的数量，指南指导的治疗没有实现疾病控制，这表明有必要， 和潜在的益处，用于治疗(S)，这些都是针对这些患者的表型而个性化的。正如下面的例子所示 聚类分析在成人和儿童中，有一组重症哮喘患者具有较少的特征 2型炎症和2型细胞因子靶向生物制品可能效果较差。孩子们住在 市中心暴露于过敏原，并对其致敏，尤其是蟑螂，从而引发2型炎症 并暴露于高水平的室内外刺激物和污染物中，可引发TH1和 Th17中性粒细胞炎症。有必要对非特应性的发病机制有更好的了解。 哮喘。以IL-6为生物标记物的全身性炎症被认为是哮喘的一种机制 严肃性。IL-6由免疫系统细胞产生，由呼吸道上皮细胞分泌，一直以来 被认为是哮喘治疗的潜在靶点。而细胞因子和可溶性受体水平以及基因 IL-6R的研究与哮喘有关，即受体在体内发出信号的内在能力 不同的表型种群没有。这项研究的目的是确定内在信号是否 蟑螂阴性、低特应性儿童和儿童对循环IL6和其他细胞因子的反应不同 蟑螂过敏症，高度特应性儿童，中度至重度哮喘。我们假设这一点 IL-6受体信号与发病率的关系。我们假设基因多态会改变 内在的IL-6信号和IL-6信号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更高内在信号的人病情恶化。 为了验证这一假设，我们提出了一项研究，旨在确定儿童内在IL-6信号的差异 患有哮喘。这项研究将包括以下儿童：1)6岁至20岁；2)有病史 持续至少一年的反复喘息/持续性哮喘；以及3)居住在 美国的内城社区。将在外周进行内在IL-6信号和SNP携带者状态的研究 基线时取血单个核细胞(PBMC)。这些研究将在鼻腔上皮细胞的一个子集上进行 参与者的数量。我们建议每隔3个月进行一次为期12个月的随访，以前瞻性地确定 IL-6信号与症状和病情加重的关系。

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.