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.

呼吸道病毒感染会引起慢性气道炎症性疾病的急性加重，例如哮喘、 慢性阻塞性肺病和囊性纤维化。然而，其背后的分子机制 人们对这些恶化的情况知之甚少。有证据表明先天免疫反应受损 涉及 Toll 样 (TLR) 受体介导。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。该提案的中心假设是病毒 TLRS 的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， 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。到 为了验证这一假设，TLRS 激活对 TLR2 和 TLRS 表达以及先天免疫功能的影响将 使用人气道上皮细胞进行检查。此外，气道炎症反应加剧 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 研究与过敏原和微生物敏感性改变有关的分子机制 激活这些受体。此外，Alternaria alternata（一种由 TLR2 检测到并已知的真菌）的影响 与新洋葱伯克霍尔德菌（一种机会性细菌）一起诱发急性哮喘发作 激活 TLRS 并导致囊性纤维化个体肺部感染将被用来探索其作用 TLR2、TLRS 和 TLRS 受体在气道炎症中的作用。正如我们对这些相互作用的理解 炎症性气道疾病的发展得到改善，旨在调节宿主的新型干预措施 可以对这些暴露做出反应，以减轻慢性炎症造成的损害。 该职业发展奖提案旨在推进我的研究培训，使其成为一名 独立科学家。为了实现这一目标，我得到了三名既定研究人员的支持 明尼苏达大学和梅奥诊所将作为共同赞助商，并提供顾问协助 我在职业发展中。我根据我在以下领域进行的实验开发了一个研究项目 相关性（参见说明）： 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， 这些恶化背后的分子机制尚不清楚。有证据表明损害- 涉及 Toll 样 (TLR) 受体介导的先天免疫反应。这个提议 表征 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。