Effects of LGM2605 on a Primate Model of Asthma

项目总结： 我们之前在小鼠身上证明了主要的致病特征(嗜酸性气道炎和 气道高反应性[AHR])显著增强的小鼠暴露在反复的社会压力和 这些变化与糖皮质激素受体(GR)表达和功能受损有关。在研究中 加州大学加利福尼亚国家灵长类研究中心非人灵长类(猕猴)的研究 戴维斯说，幼猴的焦虑气质(心理社会压力的早期表现)显著 与AHR和糖皮质激素免疫细胞无反应性有关。我们建议调查 二异落叶松脂醇二葡萄糖苷(SDG)是一种新型抗炎分子，具有天然无毒生物活性 亚麻籽成分，作为糖皮质激素抵抗型哮喘的替代/辅助疗法。SDG已证明 体内外还原、螯合和清除自由基活性及诱导核活化 红系相关因子2(NRF2)是一种主要的抗氧化剂，转录调节因子和核因子-kB的抑制因子。 我们的目标1是评估合成版本SDG(LGM2605)对呼吸道高反应性的影响 血液和支气管肺泡灌洗(BAL)免疫细胞和糖皮质激素的炎症标志物(AHR) 社会应激猕猴外周血单核细胞的功能。目标2是评估 LGM2605对GR、NF-kB和NRF2基因和表观遗传调控的影响 活组织检查。我们建议的优点和新颖性是独特的恒河猴哮喘模型系统 与心理社会应激和糖皮质激素抵抗相关，以及LGM2605的合成有效性 通过LignaMed。完成后，这些研究将为随后的第二阶段试验和 最终推广到人类临床项目。

PROJECT SUMMARY: We previously demonstrated in mice that the major pathogenic features (eosinophilic airway inflammation and airway hyperresponsiveness [AHR]) were markedly enhanced in mice exposed to repeated social stress and these changes were associated with impaired glucocorticoid receptor (GR) expression and function. In studies on non-human primates (rhesus macaques) at the California National Primate Research Center (CNPRC) at UC Davis, anxious temperament (an early manifestation of psychosocial stress) in young monkeys was significantly associated with AHR and glucocorticoid non-responsiveness of immune cells. We propose to investigate secoisolariciresinol diglucoside (SDG), a novel antiinflammatory molecule, and natural non-toxic bioactive component of flaxseed, as an alternative/adjunct therapy for glucocorticoid resistant asthma. SDG has proven reducing, chelating and free radical scavenging activities in vitro and in vivo and it induces activation of nuclear factor erythroid 2-related factor 2 (NRF2) a major anti-oxidant transcription regulator and inhibitor of NF-kB. Our aim 1 is to evaluate the effects of the synthetic version of SDG (LGM2605) on airway hyperresponsiveness (AHR), inflammatory markers of blood and bronchoalveolar lavage (BAL) immune cells and glucocorticoid function of peripheral blood mononuclear cells of socially stressed rhesus macaques. Aim 2 is to assess LGM2605 treatment on genetic and epigenetic regulation of the GR, NF-kB and NRF2 using bronchial brush biopsies. The strength and novelty of our proposal is the unique Rhesus macaque model system of asthma associated with psychosocial stress and glucocorticoid resistance, and the synthetic availability of LGM2605 through LignaMed. Upon completion, these studies will lay the groundwork for subsequent Phase II trial and ultimately to human clinical projects.