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: 7660593
• 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/7660593
• 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; Human; Immune response; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Intervention; Investigation; K-Series Research Career Programs; Lead; Ligands; Lung; Measures; Mediating; Messenger RNA; Minnesota; Molecular; Mus; Mutate; Proteins; Recombinants; Regulation; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Signal Transduction; Stimulus; TLR2 gene; Testing; Toll-like receptors; Universities; Viral; Virus Diseases; airway inflammation; base; beta-defensin-2; career development; chemokine; combat; cytokine; design; fungus; immune function; improved; in vivo; microbial; microorganism; mouse model; novel; protein expression; public health relevance; 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（由申请人提供）：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的急性加重。然而，人们对这些恶化背后的分子机制知之甚少。有证据表明，Toll 样 (TLR) 受体介导的先天免疫反应受损与此有关。微生物成分与 TLR 结合，触发信号级联，诱导炎症相关基因的表达。该提议的中心假设是，TLRS 的病毒激活使气道上皮细胞对 TLR2 刺激敏感，并使它们对 TLRS 刺激脱敏，并且这种改变的敏感性改变了气道对过敏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 激活对 TLR2 和 TLRS 表达以及先天免疫功能的影响。此外，将在用 TLR2 或 TLRS 配体治疗的野生型和 TLRS 缺陷小鼠中研究 TLRS 激活引起的气道炎症加剧，以研究与激活这些受体的过敏原和微生物敏感性改变有关的分子机制。此外，链格孢（一种由 TLR2 检测到的真菌，已知会诱发急性哮喘发作）以及新洋葱伯克霍尔德氏菌（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）的作用将被用来探索 TLR2、TLRS 和 TLRS 受体在气道炎症中的作用。随着我们对这些相互作用对炎症性气道疾病发展的了解不断加深，可以实施旨在调节宿主对这些暴露的反应的新干预措施，以减轻慢性炎症造成的损害。该职业发展奖提案旨在促进我成为一名独立科学家的研究培训。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，他们将作为共同发起人，以及协助我职业发展的顾问。我根据我在以下领域进行的实验开发了一个研究项目 公共卫生相关性（由申请人提供）：呼吸道病毒感染会引起气道疾病（哮喘、慢性阻塞性肺病和囊性纤维化）急性加重。然而，人们对这些恶化背后的分子机制知之甚少。有证据表明，Toll 样 (TLR) 受体介导的先天免疫反应受损与此有关。该提案描述了 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会导致对抗这些疾病的新干预措施。