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)

• 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
• 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

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基因的功能启动子多态性经常获得（约60％的人口是 纯合或杂合）与循环的PAI-1水平升高有关。孩子同性恋 这个等位基因的杂合子在2岁之前就患有医学治疗的呼吸道病毒疾病，有12个 病毒）至18倍（RSV）增加哮喘的风险。该关联的机制尚未建立。 p 1与气道胸腺基质淋巴细胞素（TSLP）生产有关，该生产促进了Th2型气道 回答。此外，PAI-1产生的基因型与血清IgE水平升高有关。 IgE升高增加了PDC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， 大豆异黄酮降低了TGF-1诱导的PAI-1基因表达和来自气道上皮的蛋白质产生 细胞，并且已显示出在患有哮喘的患者中降低哮喘加重的风险70％ 基因型。尚不知道补充大豆异黄酮是否会降低发展的风险 TH2气道炎症或过敏感应的可能性，如果将其施加给有哮喘风险的儿童 生命的第一年。哮喘（Sira）风险的内城市婴儿大豆异黄酮是一个单一中心， 具有PAI-1基因型的高风险婴儿的前瞻性随机，四倍的蒙版试验以比较 在峰值病毒期间与大豆染料木黄酮的补充剂量类似于大豆式摄入或安慰剂 生命第一年的季节。入学时2-6个月的儿童将随机分配给大豆异黄酮或 安慰剂在八月，从8月至3月1日接受主动治疗，然后在下一个观察 每年的队列年。该提案的目的是确定1）大豆异黄酮是否可以 调节Th2气道内型的发展，减少嗜酸性气道注射并减少 PAI-1风险基因型的高风险婴儿的致敏性，2）通过对 PAI-1，从而改善鼻病毒诱导的IFN-α反应。因此，试验的主要结果将 通过中断PAI-1/TSLP轴来开发T2气道内型。次要结果将 包括鼻PAI-1，鼻ECP，鼻细胞因子水平，血清周期，总和特定的IgE，以及 呼吸发病率。次要目的将确定PBMC是否刺激了抗病毒IFN-α反应 大豆染料木黄酮以类似的方式增强了HRV和IgE交联。 omalizumab。该目标的次要结果将评估大豆染料明亚是否会通过 PDC在类似的实验中。当前的项目使用安全且廉价的干预措施，大豆染料木黄酮， 针对通用基因型作为一种精确的医学方法，以提供对关键的更好理解 与早期过敏性气道注射的发展有关的途径。如果确认，这些结果 将导致针对临床结果的干预试验。这种询问线有可能使 有大量有患哮喘风险的儿童。