Toll-like receptor interactions and their contribution to airway inflammation

描述（由申请人提供）：呼吸道病毒感染可引起慢性气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尚不清楚。有证据表明，toll样受体介导的先天免疫反应损伤参与其中。微生物成分结合tlr触发信号级联，诱导炎症相关基因的表达。该建议的中心假设是，TLRS的病毒激活使气道上皮细胞对TLR2刺激敏感，并使其对TLRS刺激脱敏，这种改变的敏感性改变了气道对过敏原和细菌挑战的炎症反应。为了验证这一假设，我们将利用人气道上皮细胞检测TLRS激活对TLR2、TLRS表达和先天免疫功能的影响。此外，将在野生型和TLRS缺陷小鼠中研究TLRS激活后气道炎症的加重，以研究对激活这些受体的过敏原和微生物敏感性改变的分子机制。此外，交替孢霉（一种由TLR2检测到的真菌，已知可诱发急性哮喘发作）和新绿伯克霍尔德菌（一种激活TLRS并导致囊性纤维化个体肺部感染的机会性细菌）的作用将被用于探索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过程中这些相互作用的理解的提高，可以实施新的干预措施来调节宿主对这些暴露的反应，以减轻慢性炎症引起的损害。这份职业发展奖提案旨在推动我的研究训练，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的三位知名研究人员的支持，他们将作为共同发起人，以及协助我职业发展的顾问。我已经开发了一个研究项目基于我所做的实验

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.