Soy Isoflavones for Inner City Infants at Risk for Asthma (SIRA)

大豆异黄酮适用于有哮喘风险的内城婴儿 (SIRA)

基本信息

批准号：
10600115
负责人：
RAJESH KUMAR
金额：
$ 45.81万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-14 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10600115
关键词：
Absenteeism Absenteeism at work Affect Age Age Months Alleles Allergic Antiviral Response Asthma Attenuated CCL17 gene CCL24 gene Canis familiaris Cells Child Childhood Asthma Clinical Dendritic Cells Development Dictyoptera Dietary Administration Dose Emergency department visit Enrollment Eosinophil cationic protein Eosinophilia Epithelial Cells Family Feedback Felis catus Gene Expression Gene Proteins Genes Genetic Polymorphism Genetic Variation Genistein Genotype Heterozygote Homo Hospitalization Human Hypersensitivity IgE Immunoglobulin Class Switching Individual Infant Inflammation Influentials Ingestion Interferon Type I Interferon alpha Interruption Intervention Intervention Trial Lead Life Masks Measures Medical Nose Nutritional Outcome Pathway interactions Pattern Peripheral Blood Mononuclear Cell Placebos Plasma Plasminogen Activator Inhibitor 1 Population Prevention Prevention strategy Production Randomized Research Project Grants Rhinovirus Risk Sampling Schools Seasons Serum Small inducible cytokine A24 Societies Supplementation Surface TLR3 gene TSLP gene Th2 Cells Time Viral Viral Load result Virus Visit Work active method aged airborne allergen airway epithelium airway inflammation airway remodeling allergic airway inflammation asthma exacerbation asthma prevention asthmatic airway chemokine cohort cost crosslink cytokine eosinophil experimental study gain of function genetic variant high risk infant improved indoor allergen inhibitor inner city mast cell nasal swab omalizumab periostin placebo group precision medicine primary outcome promoter prospective pulmonary function recruit respiratory respiratory morbidity response restoration risk variant secondary outcome soy soy protein isolate

项目摘要

Abstract: A frequent gain of function promoter polymorphism for the PAI-1 gene (~60% of the population are homozygous or heterozygous) is associated with elevated circulating PAI-1 levels. Children homo or heterozygous for this allele who had a medically attended respiratory viral illness before age 2, had a 12 (any virus) to 18-fold (RSV) increased risk of asthma. The mechanisms for this association are not established. PAI- 1 is associated with airway thymic stromal lymphopoietin (TSLP) production, which promotes Th2 type airway responses. Furthermore, the PAI-1 overproducing genotype is associated with increased serum levels of IgE. IgE elevation increases FcεRI levels on pDCs which attenuates type I interferon antiviral responses. Of note, soy isoflavones reduce TGF-1-induced PAI-1 gene expression and protein production from airway epithelial cells, and have been shown to decrease the risk of asthma exacerbations by 70% in individuals with the genotype. It is not known whether supplementation with soy isoflavones will decrease the risk of developing Th2 airway inflammation or the likelihood of allergic sensitization if it is given to children at risk of asthma in the first year of life. Soy Isoflavones for Inner City Infants at Risk for Asthma (SIRA) is a single center, prospective randomized, quadruple masked trial of high-risk infants with the PAI-1 genotype to compare supplementation with soy genistein at doses similar to soy formula ingestion or placebo during peak viral season of the first year of life. Children aged 2-6 months at enrollment will be randomized to soy isoflavone or placebo in August, receiving active treatment from August to March 1st, followed by observation over the next year for each yearly cohort. The objective of this proposal is to determine 1) whether soy isoflavones can modulate development of Th2 airway endotypes, decrease eosinophilic airway inflammation, and reduce sensitization in high risk infants with the PAI-1 risk genotype, and 2) decrease IgE production via effects on PAI-1, and thereby improve rhinovirus-induced IFN-α response. As such, the primary outcome of the trial will be the development of T2 airway endotypes by interrupting the PAI-1/TSLP axis. Secondary outcomes will include nasal PAI-1, nasal ECP, nasal Th2 cytokine levels, serum periostin, total and specific IgE, and respiratory morbidity. The secondary aim will determine if antiviral IFN-α responses by PBMC stimulated by HRV and IgE crosslinking are augmented by soy genistein in a similar fashion as has been described for omalizumab. Secondary outcomes for this aim will evaluate if soy genistein will augment IFN-α responses by pDC in similar experiments. The current project uses a safe and inexpensive intervention, soy genistein, directed to a common genotype as a precision medicine approach to provide a better understanding of key pathways relevant to development of allergic airway inflammation in early life. If confirmatory, these results would lead into intervention trials focused on clinical outcomes. This line of inquiry has the potential to benefit a large number of children at risk of developing asthma.

抽象的： PAI-1 基因频繁获得功能启动子多态性（约 60% 的人群是纯合子或杂合子）与循环 PAI-1 水平升高相关。该等位基因的杂合子，在 2 岁之前患有呼吸道病毒疾病并接受治疗，其 12（任何病毒）使哮喘风险增加 18 倍。这种关联的机制尚未确定。 1 与气道胸腺基质淋巴细胞生成素 (TSLP) 的产生相关，可促进 Th2 型气道此外，PAI-1 过量产生的基因型与血清 IgE 水平升高有关。 IgE 升高会增加 pDC 上的 FcεRI 水平，从而减弱 I 型干扰素抗病毒反应。大豆异黄酮减少 TGF-β1 诱导的 PAI-1 基因表达和气道上皮蛋白的产生细胞，并已被证明可以将哮喘患者的哮喘恶化风险降低 70% 目前尚不清楚补充大豆异黄酮是否会降低患病风险。如果给有哮喘风险的儿童使用，可能会出现 Th2 气道炎症或过敏反应。生命第一年的大豆异黄酮治疗内城婴儿哮喘风险 (SIRA) 是一个单一中心，对具有 PAI-1 基因型的高危婴儿进行的前瞻性随机、四重屏蔽试验进行比较在病毒高峰期补充大豆金雀异黄酮，剂量与大豆配方奶粉摄入相似或安慰剂入组时 2-6 个月大的儿童将被随机分配服用大豆异黄酮或 8月服用安慰剂，8月至3月1日接受积极治疗，随后观察接下来的时间该提案的目标是确定 1) 大豆异黄酮是否可以调节 Th2 气道内型的发展，减少嗜酸性粒细胞气道炎症，并减少具有 PAI-1 风险基因型的高危婴儿的致敏作用，以及 2) 通过影响来减少 IgE 的产生 PAI-1，并改善鼻病毒诱导的 IFN-α 反应，因此，该试验的主要结果将是。次要结果是通过中断 PAI-1/TSLP 轴来发展 T2 气道内型。包括鼻部 PAI-1、鼻部 ECP、鼻部 Th2 细胞因子水平、血清骨膜素、总 IgE 和特异性 IgE，以及次要目标是确定 PBMC 的抗病毒 IFN-α 反应是否受到刺激。 HRV 和 IgE 交联通过大豆金雀异黄素以类似的方式增强，如已描述的该目标的次要结果将评估大豆金雀异黄素是否会通过以下方式增强 IFN-α 反应： pDC 在类似的实验中使用了安全且廉价的干预措施，即大豆金雀异黄素，将通用基因型作为精准医学方法，以更好地理解关键基因型如果得到证实，这些结果将揭示生命早期过敏性气道炎症发展的相关途径。将导致关注临床结果的干预试验有可能使患者受益。大量儿童面临患哮喘的风险。