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

基本信息

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
项目类别：
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

项目摘要

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，慢性阻塞性肺部疾病和囊性纤维化）的急性加重。但是，这些加重的基础的分子机制知之甚少。有证据表明，涉及Toll样受体介导的先天免疫反应受损。微生物成分结合TLRS触发信号级联，诱导涉及炎症的基因表达。该提议的中心假设是，TLR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，这种修饰的敏感性改变了气道对过敏原和细菌挑战的炎症反应。为了检验这一假设，将使用人类气道上皮细胞检查TLRS激活对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缺陷的小鼠中研究气道炎症对TLRS激活的响应加剧，以研究对激活这些受体敏感性改变敏感性的分子机制。此外，替代品的替代品的作用，一种由TLR2检测到的真菌，并已知会诱导急性哮喘发作，以及Burkholderia cenocepacia，一种机会性细菌，一种激活TLR并引起囊肿纤维化患者的肺部感染的机会，将用于囊肿的感觉，以探索tlrs的作用，并探索TLRS的作用Tlrs and tlrs tlrs tlrs tlrs tlrs tlrs and tlrs tlrs tlrs and tlrs。随着我们对炎症性气道疾病发展的这些相互作用的理解改善，旨在调节宿主对这些暴露的反应的新干预措施可以实施，以减轻慢性炎症造成的损害。该职业发展奖提案旨在将我的研究培训推向成为一名独立科学家。为了实现这一目标，1获得了明尼苏达大学和梅奥诊所的三名既定调查员的支持，该诊所将作为共同发起人以及顾问，以帮助我进行职业发展。我根据我在公共卫生相关性（由申请人提供）：呼吸道病毒感染引起气道疾病（哮喘，COPD和CF）的严重加剧。但是，这些加重的分子机制知之甚少。有证据表明，涉及Toll样受体（TLR）受体介导的先天免疫反应受损。该建议表征了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。