Effects of LGM2605 on a Primate Model of Asthma

LGM2605 对灵长类哮喘模型的影响

基本信息

批准号：
9347326
负责人：
ANGELA HACZKU
金额：
$ 27.78万
依托单位：
LIGNAMED, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-18 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9347326
关键词：
Aftercare Allergic Animals Anti-Inflammatory Agents Antioxidants Anxiety Area Asthma Biological Biological Models Biopsy Biopsy Specimen Blood Brain Bronchoalveolar Lavage California Cells Chelating Agents Child Chronic Clinical DNA Methylation Disease Effectiveness Epigenetic Process Exhibits Flax Free Radical Scavenging Genes Genetic Genetic Transcription Global Change Glucocorticoid Receptor Glucocorticoids High Pressure Liquid Chromatography Histone H3 Human Immune Impairment Inflammatory Investigation Lead Lysine Macaca mulatta Modeling Monkeys Mus NF-kappa B NR3C1 gene Natural Products Pathogenicity Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Phylogenetic Analysis Play Predisposition Prevalence Price Primates Production Property Psychosocial Stress Receptor Gene Research Resistance Rodent Role Stress Testing Work airway hyperresponsiveness airway inflammation anxious temperament asthmatic patient cohort epigenetic regulation flaxseed lignan in vitro activity in vivo inflammatory marker inhibitor/antagonist methylation pattern nonhuman primate novel nuclear factor-erythroid 2 peripheral blood phase II trial promoter psychosocial receptor expression receptor function scale up secoisolariciresinol social stress transcription factor

项目摘要

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.

项目概要：我们之前在小鼠中证明了主要的致病特征（嗜酸性气道炎症和暴露于反复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州国家灵长类动物研究中心 (CNPRC) 对非人类灵长类动物（恒河猴）的研究 Davis 认为，幼猴的焦虑气质（心理社会压力的早期表现）显着与 AHR 和免疫细胞的糖皮质激素无反应有关。我们建议调查开环异落叶松树脂醇二葡萄糖苷 (SDG)，一种新型抗炎分子，具有天然无毒的生物活性亚麻籽的成分，作为糖皮质激素耐药性哮喘的替代/辅助疗法。可持续发展目标已经证明在体外和体内具有还原、螯合和自由基清除活性，并诱导核激活红细胞因子 2 相关因子 2 (NRF2) 是一种主要的抗氧化转录调节剂和 NF-kB 抑制剂。我们的目标 1 是评估合成版 SDG (LGM2605) 对气道高反应性的影响 (AHR)、血液和支气管肺泡灌洗液 (BAL) 免疫细胞和糖皮质激素的炎症标志物社会应激恒河猴外周血单核细胞的功能。目标 2 是评估 LGM2605 使用支气管刷治疗对 GR、NF-kB 和 NRF2 的遗传和表观遗传调控活检。我们提案的优势和新颖之处在于独特的恒河猴哮喘模型系统与心理社会压力和糖皮质激素抵抗以及 LGM2605 的合成可用性相关通过 LignaMed。完成后，这些研究将为后续的二期试验奠定基础最终走向人类临床项目。