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: 8253705
• 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/8253705
• 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; Goals; Human; Immune response; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Instruction; Intervention; Investigation; Lead; Ligands; Lung; Measures; Mediating; Minnesota; Molecular; Mus; Mutate; Proteins; Recombinants; Regulation; Research; Research Personnel; Research Project Grants; Role; Scientist; Signal Transduction; Stimulus; TLR2 gene; TLR3 gene; Testing; Toll-like receptors; Viral; Virus Diseases; airway inflammation; base; beta-defensin-2; career; 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

Respiratory viral infections elicit acute exacerbations of chronicairway inflammatory diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis. However,the molecularmechanisms thatunderlie these exacerbations are poorly understood. Evidencesuggests that impairment of innate immune responses mediated by Toll-like (TLR)receptors is involved.Microbial components bind TLRs triggering signaling cascades that induce expression ofgenes involvedin 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 immunefunction 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, alongwith 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 DevelopmentAward proposal was designed to advance my research trainingtowards becoming an independent scientist. To accomplish this goal 1 have received the support of three established investigators at the Universityof 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 RELEVANCE (See instructions): Respiratory viral infections elicit acute exacerbations of airway diseases (asthma, COPD and CF). However, molecular mechanisms underlying these exacerbations are poorly understood. Evidence suggests impair- ment 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.

呼吸道病毒感染引起慢性炎症性疾病（例如哮喘）的急性加重 慢性阻塞性肺部疾病和囊性纤维化。但是，分子机制伸出来 这些加剧的理解很少。证明了损害先天免疫反应的障碍 涉及Toll样（TLR）受体介导 诱导涉及炎症的基因表达。该提议的中心假设是病毒 TLR的激活使气道上皮细胞对TLR2刺激敏感，并使它们脱敏TLRS刺激和 这种修改的灵敏度改变了气道对过敏原和细菌挑战的炎症反应。到 检验这一假设，TLRS激活对TLR2和TLRS表达和先天免疫功能的影响将会 使用人气道上皮细胞检查。此外，对气道炎症的加剧响应 将在用TLR2或TLRS配体处理的野生型和TLRS缺乏小鼠中研究TLRS激活 研究涉及改变过敏原和微生物敏感性的分子机制， 激活这些受体。此外，替代品的作用，TLR2检测到的真菌和已知的真菌 诱发急性哮喘发作，以及Burkholderia cenocepacia，这是一种机会性细菌 活化的TLR并引起囊性纤维化个体的肺部感染 气道炎症中的OFTLR2，TLR和TLRS受体。随着我们对这些互动的理解 炎症性气道疾病的发展改善，旨在调节宿主的新型干预措施 可以实施对这些暴露的反应，以减轻慢性炎症造成的损害。 这项职业发展的提案旨在推动我的研究培训towards成为一个 独立科学家。为了实现这一目标1，1在 明尼苏达州大学和梅奥诊所将作为共同发起人以及顾问协助 我的职业发展。我根据我在 相关性（请参阅说明）： 呼吸道病毒感染引起气道疾病（哮喘，COPD和CF）的急性加重。然而， 这些加重的分子机制知之甚少。有证据表明损害 涉及Toll样受体（TLR）受体介导的先天免疫反应的预测。这个建议 表征TLRS激活对TLR2和TLR的表达和功能的影响。 了解这些相互作用可能会导致新的干预措施与这些疾病作斗争。