Toll-like receptor interactions and their contribution to airway inflammation

Toll 样受体相互作用及其对气道炎症的贡献

• 批准号: 8056630
• 负责人: Tamene Melkamu
• 金额: $ 12.72万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8056630
• 关键词: Acute; Allergens; Alternaria; Asthma; Bacteria; Binding; Burkholderia; Cells; Chronic; Chronic Obstructive Airway Disease; Clinic; Cystic Fibrosis; Development; Disease; Double-Stranded RNA; Epithelial Cells; Exposure to; Flagella; Flagellin; Gene Expression; Goals; Health; Human; Immune response; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; K-Series Research Career Programs; Lead; Ligands; Lung; Measures; Mediating; Minnesota; Molecular; Mus; Mutate; Proteins; Recombinants; Regulation; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Signal Transduction; Stimulus; TLR2 gene; TLR3 gene; Testing; Toll-like receptors; Universities; Viral; Virus Diseases; airway inflammation; base; beta-defensin-2; career development; chemokine; combat; cytokine; design; fungus; improved; in vivo; innate immune function; mRNA Expression; microbial; microorganism; mouse model; novel; protein expression; receptor; research study; respiratory; response; therapy design

DESCRIPTION (provided by applicant): Respiratory viral infections elicit acute exacerbations of chronic airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. However, the molecular mechanisms that underlie these exacerbations are poorly understood. Evidence suggests that impairment of innate immune responses mediated by Toll-like (TLR) receptors is involved. Microbial components bind TLRs triggering signaling cascades that induce expression of genes involved in inflammation. The central hypothesis of this proposal is that viral activation of TLRS sensitizes airway epithelial cells to TLR2 stimuli and desensitizes them to TLRS stimuli and this modified sensitivity alters the inflammatory response of the airways to allergen and bacterial challenge. To test this hypothesis, the effect of TLRS activation on TLR2 and TLRS expression and innate immune function will be examined using human airway epithelial cells. Moreover, exacerbation of airway inflammation in response to TLRS activation will be studied in wild-type and TLRS-deficient mice treated with TLR2 or TLRS ligands to investigate the molecular mechanisms involved in altered sensitivity to allergens and microorganisms that activate these receptors. Additionally, the effects of Alternaria alternata, a fungus detected by TLR2 and known to induce acute asthmatic episodes, along with Burkholderia cenocepacia, an opportunistic bacterium that activated TLRS and causes pulmonary infection in individuals with cystic fibrosis will be used to explore the role ofTLR2, TLRS, and TLRS receptors in airway inflammation. As our understanding of these interactions on the development of inflammatory airway disease improves, novel interventions designed to modulate the host response to these exposures can be implemented to alleviate the damage caused by chronic inflammation. This Career Development Award proposal was designed to advance my research training towards becoming an independent scientist. To accomplish this goal 1 have received the support of three established investigators at the University of Minnesota and the Mayo Clinic that will serve as co-sponsors, along with consultants to assist me in my career development. I have developed a research project based on experiments I performed in the PUBLIC HEALTH RELEVANCE (provided by applicant): Respiratory viral infections elicit acute exacerbations of airway diseases (asthma, COPD and CF). However, molecular mechanisms underlying these exacerbations are poorly understood. Evidence suggests impairment of innate immune responses mediated by Toll-like (TLR) receptors is involved. This proposal characterizes the effects of TLRS activation on the expression and function of TLR2 and TLRS. Understanding these interactions may lead to novel interventions to combat these diseases.

描述(申请人提供)：呼吸道病毒感染引起慢性呼吸道炎症性疾病的急性加重，如哮喘、慢性阻塞性肺疾病和囊性纤维化。然而，这些恶化背后的分子机制却知之甚少。有证据表明，Toll样受体(Toll-like，TLR)受体介导的先天免疫反应受损也参与其中。微生物成分与TLR结合，触发信号级联反应，诱导炎症相关基因的表达。这一建议的中心假设是TLRs的病毒激活使呼吸道上皮细胞对TLR2刺激敏感，并使它们对TLRs刺激不敏感，这种修改的敏感性改变了呼吸道对变应原和细菌攻击的炎症反应。为了验证这一假说，将使用人呼吸道上皮细胞来检测TLRs激活对TLR2和TLRs表达以及天然免疫功能的影响。此外，将在使用TLR2或TLRs配体治疗的野生型和TLRs缺陷小鼠中研究TLRs激活引起的呼吸道炎症加剧，以探讨激活这些受体的过敏原和微生物敏感性改变所涉及的分子机制。此外，TLR2检测到的一种引起急性哮喘发作的真菌互隔交链孢霉，以及一种激活TLRs并导致囊性纤维化患者肺部感染的机会性细菌cenocepacia，将被用来探索TLR2、TLRs和TLRs受体在呼吸道炎症中的作用。随着我们对炎症性呼吸道疾病发展过程中这些相互作用的了解的加深，可以实施旨在调节宿主对这些暴露的反应的新的干预措施，以减轻慢性炎症造成的损害。这项职业发展奖的提议旨在推动我的研究培训，使我成为一名独立的科学家。为了实现这一目标，我得到了明尼苏达大学和梅奥诊所三名资深研究人员的支持，他们将作为共同赞助商，以及帮助我职业发展的顾问。我已经开发了一个基于我在 公共卫生相关性(由申请人提供)：呼吸道病毒感染可引起呼吸道疾病(哮喘、慢性阻塞性肺病和慢性阻塞性肺疾病)的急性加重。然而，这些恶化背后的分子机制却知之甚少。有证据表明，Toll样受体(Toll-like，TLR)受体介导的先天免疫反应受损。本研究描述了TLRs激活对TLR2和TLRs表达和功能的影响。了解这些相互作用可能导致抗击这些疾病的新干预措施。