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

摘要： PAI-1基因功能启动子多态性的频繁获得(约60%的人群是 纯合子或杂合子)与循环PAI-1水平升高相关。儿童同性恋或 这个杂合子的等位基因在2岁之前有过呼吸道病毒疾病，有12(任何 呼吸道合胞病毒(RSV)使患哮喘的风险增加18倍。这种联系的机制尚未建立。派-- 1与呼吸道胸腺间质淋巴生成素(TSLP)的产生有关，TSLP促进Th2型呼吸道 回应。此外，PAI-1过度产生的基因与血清IgE水平升高有关。 IgE升高可增加PDCs上的FcεRI水平，从而减弱I型干扰素抗病毒反应。值得注意的是， 大豆异黄酮降低转化生长因子--1诱导的呼吸道上皮细胞PAI-1基因表达和蛋白合成 细胞，并已被证明可将患有哮喘的个体的哮喘恶化风险降低70%。 基因分型。目前尚不清楚补充大豆异黄酮是否会降低罹患癌症的风险。 Th2呼吸道炎症或过敏性过敏的可能性，如果给有哮喘风险的儿童服用 生命的第一年。针对内城哮喘高危婴儿的大豆异黄酮(SIRA)是一个单一中心， 具有PAI-1基因高危婴儿的前瞻性、随机、四重掩蔽试验比较 病毒高峰期补充大豆金雀异黄素的剂量与大豆配方奶粉或安慰剂相似 生命第一年的季节。注册时2-6个月大的儿童将被随机分配到大豆异黄酮组或 8月服用安慰剂，8月至3月1日接受积极治疗，随后观察下一年 每一年度队列为一年。这项提案的目的是确定1)大豆异黄酮类化合物是否可以 调节Th2气道型发展，减少嗜酸性气道炎，减少 PAI-1风险基因高危婴儿的致敏作用，以及2)通过影响 PAI-1，从而提高鼻病毒诱导的干扰素-α应答。因此，审判的主要结果将是 通过阻断PAI-1/TSLP轴，导致T2气道内型的形成。次要结果将是 包括鼻腔PAI-1、鼻腔ECP、鼻腔Th2细胞因子水平、血清Periostin、总和特异性IgE以及 呼吸道疾病。第二个目标将确定是否有抗病毒干扰素-α反应的PBMC刺激 大豆染料木素以类似于已描述的方式增强HRV和IgE的交联性 奥马珠单抗。这一目标的次要结果将评估大豆染料木素是否会通过以下方式增强干扰素-α反应 PDC在类似的实验中。目前的项目使用了一种安全且廉价的干预措施--大豆染料木素， 针对一种常见的基因分型作为精准医学的一种方法，提供了更好的理解关键 与早期过敏性呼吸道炎症发展相关的途径。如果是确凿的，这些结果 将导致关注临床结果的干预试验。这条调查路线有可能使 有大量儿童有患哮喘的风险。

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.