CAUSE Clinical Research Center New York (CAUSE-CRC)

纽约 CAUSE 临床研究中心 (CAUSE-CRC)

• 批准号: 10396655
• 负责人: Meyer Kattan
• 金额: $ 46.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-22 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10396655
• 关键词: Accounting; Address; Adult; Affect; Age; Air Pollution; Allergens; Allergic; Asthma; Biological Markers; Biological Products; Cells; Censuses; Characteristics; Child; Childhood Asthma; Clinical Research; Clinical Trials; Cluster Analysis; Code; Communities; Coupled; Development; Dictyoptera; Disease; Environment; Environmental Exposure; Epithelial Cells; Exposure to; Genetic; Genetic Polymorphism; Genetic study; Goals; Guidelines; Hypersensitivity; IL6 gene; IgE; Immune system; Impairment; Individual; Individual Differences; Inflammation; Inflammatory Response; Interleukin 6 Receptor; Interleukin-1; Interleukin-2; Interleukin-6; Interleukins; Investigation; Irritants; Knowledge; Lead; Low income; Measures; Mediating; Medical center; Mendelian disorder; Molecular; Morbidity - disease rate; Nasal Epithelium; National Institute of Allergy and Infectious Disease; New York; New York City; Nitrogen Dioxide; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Pollution; Population; Prevention approach; Production; Protocols documentation; Receptor Signaling; Recording of previous events; Recurrence; Research; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Resources; Role; Sampling; Severities; Severity of illness; Signal Transduction; Site; Stress; Symptoms; Testing; Universities; Urban Community; Variant; Wheezing; airway epithelium; asthmatic; asthmatic patient; atopy; base; carrier status; clinical phenotype; cytokine; disorder control; experience; follow-up; improved; indexing; indoor concentrations; inner city; neutrophil; new therapeutic target; novel therapeutic intervention; pollutant; programs; prospective; receptor; receptor binding; response; systemic inflammatory response; urban setting

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.

项目总结/摘要 儿童哮喘对生活在城市社区的儿童的影响不成比例，部分原因是环境因素 暴露于过敏原、压力和空气污染。本项目建立临床研究中心， 以开发有效哮喘为最终目标的网络范围和特定地点的临床研究和试验 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。很大 一些哮喘患者，指南指导的治疗没有达到疾病控制，提示需要， 和潜在的益处。正如 在成人和儿童的聚类分析中，有一组严重的哮喘患者， 2型炎症，并且在其中2型靶向精氨酸的生物制剂可能不太有效。的儿童 市中心暴露于过敏原，特别是蟑螂，引发2型炎症 反应和暴露于高水平的室内和室外刺激物和污染物，可触发TH1和 TH17嗜中性炎症。需要更好地了解非特应性 哮喘以IL-6为生物标志物的全身性炎症被认为是介导哮喘的一种机制 严重性。IL-6由免疫系统的细胞产生并由气道上皮细胞分泌， 作为哮喘治疗的潜在靶点。而细胞因子和可溶性受体水平，以及遗传 IL-6R的研究已经检查了与哮喘的关系，受体内在的能力， 不同的表型种群却没有。本研究的目的是确定是否内在信号 对循环IL 6和其他细胞因子的反应在蟑螂阴性、低特应性儿童和 蟑螂过敏，高度特应性儿童中度至重度哮喘。我们假设 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IL-6信号传导和IL-6信号传导将是发病率决定因素。该方案将探索性测试 假设污染和压力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，我们提出了一项旨在确定儿童内在IL-6信号传导差异的研究 哮喘该研究将包括以下儿童：1）年龄在6至20岁之间; 2）有病史 至少持续一年的反复喘息/持续性哮喘; 3）生活在低收入人口普查区， 美国市中心社区将在外周血中进行内源性IL-6信号传导和SNP携带状态的研究。 基线时的血液单核细胞（PBMC）。这些研究将在鼻上皮细胞的一个子集上进行 的参与者。我们建议每隔3个月进行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。