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

摘要： 派-1基因的功能启动子多态性的频繁获得（约60%的人群是 纯合或杂合）与升高的循环派-1水平相关。儿童同性恋或 对于该等位基因的杂合子，在2岁之前患有呼吸道病毒性疾病的患者， 病毒）至18倍（RSV）增加哮喘的风险。这种联系的机制尚未建立。派- 1与气道胸腺基质淋巴细胞生成素（TSLP）的产生有关，TSLP促进Th 2型气道 应答此外，派-1过度产生的基因型与血清IgE水平升高相关。 IgE升高增加pDC上的FcεRI水平，其减弱I型干扰素抗病毒应答。值得注意的是， 大豆异黄酮降低TGF-β 1诱导气道上皮派-1基因表达和蛋白质产生 细胞，并已被证明可以降低哮喘急性发作的风险70%，在个人与 基因型目前尚不清楚补充大豆异黄酮是否会降低患上糖尿病的风险。 Th 2气道炎症或过敏性致敏的可能性，如果给予有哮喘风险的儿童， 生命的第一年。大豆异黄酮用于有哮喘风险的内城婴儿（SIRA）是一个单一的中心， 在派-1基因型高危婴儿中进行的前瞻性随机、四盲试验， 在病毒高峰期以类似于大豆配方摄入或安慰剂的剂量补充大豆染料木黄酮 生命第一年的季节。入组时年龄为2-6个月的儿童将随机接受大豆蛋白或 8月给予安慰剂，8月至3月1日接受积极治疗，随后观察 每一年，每一年，本提案的目的是确定1）大豆异黄酮是否可以 调节Th 2气道内型的发展，减少嗜酸性气道炎症， 在具有派-1风险基因型的高风险婴儿中致敏，和2）通过影响 派-1，从而改善鼻病毒诱导的IFN-α应答。因此，试验的主要结果将 通过阻断派-1/TSLP轴而发展T2气道内型。次要结局将 包括鼻派-1、鼻ECP、鼻Th 2细胞因子水平、血清骨膜蛋白、总IgE和特异性IgE， 呼吸道疾病第二个目的是确定PBMC刺激的抗病毒IFN-α应答是否由 HRV和IgE交联通过大豆染料木黄酮以与已经描述的类似的方式增强。 奥马珠单抗。该目标的次要结果将评估大豆染料木黄酮是否会通过以下方式增强IFN-α应答： pDC在类似的实验中。目前的项目使用一种安全而廉价的干预措施，大豆染料木素， 针对一个共同的基因型作为一种精确的医学方法，以提供更好的理解的关键 与生命早期过敏性气道炎症发展相关的通路。如果确认，这些结果 会导致以临床结果为重点的干预试验。这条调查路线有可能使一个 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.