Toll-like receptor interactions and their contribution to airway inflammation

描述（由申请方提供）：呼吸道病毒感染引起慢性气道炎症性疾病（如哮喘、慢性阻塞性肺病和囊性纤维化）急性加重。然而，这些恶化的分子机制知之甚少。有证据表明，由Toll样（TLR）受体介导的先天性免疫反应的损害是相关的。微生物组分结合TLR，触发诱导炎症相关基因表达的信号级联。该提议的中心假设是TLRS的病毒活化使气道上皮细胞对TLR2刺激物敏感并使它们对TLRS刺激物脱敏，并且这种改变的敏感性改变气道对变应原和细菌攻击的炎症反应。为了检验这一假设，将使用人气道上皮细胞检查TLRS活化对TLR2和TLRS表达和先天免疫功能的影响。此外，将在用TLR2或TLRS配体处理的野生型和TLRS缺陷小鼠中研究响应于TLRS激活的气道炎症的恶化，以研究涉及对激活这些受体的过敏原和微生物的敏感性改变的分子机制。此外，通过TLR2检测到的已知可诱导急性哮喘发作的链格孢菌（Alternaria alternata），沿着新洋葱伯克霍尔德菌（Burkholderia cenocepacia）（一种可激活TLRS并导致囊性纤维化患者肺部感染的机会性细菌）的作用，将用于探索TLR2、TLRS和TLRS受体在气道炎症中的作用。随着我们对炎症性气道疾病发展的这些相互作用的理解的提高，可以实施旨在调节宿主对这些暴露的反应的新型干预措施，以减轻慢性炎症引起的损伤。这个职业发展奖的建议是为了推进我的研究训练，成为一个独立的科学家。为了实现这一目标，我得到了明尼苏达大学和马约诊所的三位资深研究人员的支持，他们将作为共同赞助商，沿着的还有顾问，以帮助我的职业发展。我已经开发了一个研究项目的基础上进行的实验，我在 公共卫生相关性（由申请方提供）：呼吸道病毒感染引起气道疾病（哮喘、COPD和CF）急性加重。然而，这些恶化的分子机制知之甚少。有证据表明，由Toll样（TLR）受体介导的先天性免疫应答受损。该提议表征了TLRS激活对TLR2和TLRS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来对抗这些疾病。

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.