Project 3 - Mechanistic Discovery of CAM Therapies for Asthma

项目 3 - 哮喘 CAM 疗法的机制发现

• 批准号: 7279762
• 负责人: Quing Jiang
• 金额: $ 17.58万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7279762
• 关键词: alternative medicine; antiinflammatory agents; antioxidants; asthma; drug screening /evaluation; eicosanoids; eosinophil; flavonoids; gel mobility shift assay; lipoxygenase; membrane channels; mitogen activated protein kinase; myeloperoxidase; nuclear factor kappa beta; pharmacokinetics; prostaglandin endoperoxide synthase; respiratory disease /disorder therapy; therapy design /development; tissue /cell culture; tocopherols

Asthma is a chronic inflammatory disease of the respiratory airways and is becoming epidemic in the United States. Oxidative stress plays an important role in exacerbation of airway inflammation and overall disease symptom. Although it has been shown that the levels of vitamin E and ascorbate were decreased in asthmatics, the potential to use antioxidants in the therapy of asthma has not been well explored. The proposed studies in project 3 is part of the synergistic effort for investigating the utility of natural antioxidants as complementary and alternative medicines (CAMs) in the treatment of asthma. During inflammation, several pro-inflammatory mediators including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), cytokines and chmokines, play central roles in regulating inflammatory response and asthma. We propose to use various forms of vitamin E and polyphenols as the starting candidates based on the recent studies by us and the others. We have discovered that gamma-tocopherol, the major form of vitamin E in diets, has anti-inflammatory activity by inhibiting PGE2 and LTB4 as well as TNF-a. It has been shown that polyphenols like genistein and resveratrol potentiate the cytokine expression in certain cellular system through NF-kappaB regulated gene expression. In addition, ascorbate, genistein and reseveratrol exhibit beneficial effects on regulating airway epithelial fluid secretion. These observations lead to the current hypothesis that these natural antioxidants, and their combinations may be useful as CAMs in the treatment of asthma. Project 3 aims to discover candidate CAM therapies on a molecular, cellular and mechanistic basis to assess the ability of potential CAMs to inhibit oxidative damage from myeloperoxidase and eosinophil peroxidase, generation of eicosanoids by cyclooxygenase and lipoxygenase, NF-kappaB and MAP kinase mediated gene regulation and cytokine formation, and to modulate Na+ and CI- ion channels, transepithelial barrier function and H+ conductive pathways of the airway epithelium. Our studies will provide the scientific basis for our collaborators, Drs Wagner & Harkema at MSU to test CAMs in rodent models and Drs Peden, Alexis, Bromberg & Patel at UNC in Phase I Clinical Screening of CAMs therapy.

哮喘是呼吸道气道的慢性炎症性疾病，在美国流行。氧化应激在加剧气道炎症和整体疾病症状方面起着重要作用。尽管已经表明，哮喘患者的维生素E和抗坏血酸水平降低，但在哮喘治疗中使用抗氧化剂的潜力尚未得到很好的探索。项目3中提出的研究是研究哮喘治疗自然抗氧化剂作为补充和替代药物（CAM）的协同工作的一部分。在炎症期间，包括前列腺素E2（PGE2）和白三烯B4（LTB4），细胞因子和Chmokines在内的几种促炎性介质在调节炎症反应和哮喘中起着核心作用。我们建议将各种形式的维生素E和多酚用作为我们和其他研究的最新研究。我们已经发现伽玛托酚， 维生素E在饮食中的主要形式通过抑制PGE2和LTB4以及TNF-A具有抗炎活性。已经表明，诸如染料木黄酮和白藜芦醇等多酚通过NF-kappab调节的基因表达在某些细胞系统中增强了细胞因子的表达。此外，抗坏血酸盐，染料木黄酮和重生对调节气道上皮流体分泌具有有益的作用。这些观察结果导致了当前的假设，即这些天然抗氧化剂及其组合可能在治疗哮喘的治疗中有用。项目3旨在通过分子，细胞和机械基础发现候选CAM疗法，以评估潜在CAM抑制骨过氧化物酶和嗜酸性粒细胞过氧化物酶的氧化损伤的能力，通过环氧酶和脂肪氧合酶和脂肪氧合酶，NF-Kappab和nf-kappab和Medee nae+ Gene的Genemations Nae+ Gene构造，eicosanoid的产生气道上皮的离子通道，旋转屏障功能和H+导电途径。我们的研究将为我们的合作者，MSU的合作者提供科学基础，以测试啮齿动物模型中的CAM，并在INC的INC中，在INC的INC中，INC的INC临床筛查CAMS治疗。