Airway Epithelial Adaptation to Infectious Stimuli

气道上皮对感染刺激的适应

基本信息

批准号：
7392300
负责人：
Scott H Randell
金额：
$ 34.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7392300
关键词：
Agar Amplifiers Anti-Inflammatory Agents Anti-inflammatory Area Biochemical Biological Models Blood Circulation Breeding Candidate Disease Gene Cell Line Cells Chronic Chronic Bronchitis Cystic Fibrosis Disease Dominant-Negative Mutation Environment Epithelial Epithelial Cells Equilibrium Feedback Genes Genetic Transcription Goals Homeostasis Host Defense Human Immune response Infection Inflammation Inflammatory Inflammatory Response Lung Mitogen-Activated Protein Kinases Modeling Molecular Mucous body substance Mus Phosphotransferases Production Proteins Pseudomonas Pseudomonas aeruginosa Receptor Signaling Regulation Reporter Respiratory System Risk Role Screening procedure Secondary to Signal Pathway Signal Transduction Signal Transduction Pathway Stimulus Testing Therapeutic Toll-Like Receptor Pathway Toll-like receptors Tracheobronchial Transcription Factor AP-1 Transgenic Mice Zinc Fingers airway epithelium airway inflammation base cytokine design epithelial Na+ channel functional outcomes human IRAK3 protein in vivo in vivo Model inhibitor/antagonist knock-down microbial mouse model novel novel strategies pathogen response sensor

项目摘要

DESCRIPTION (provided by applicant): Strategically interposed between the environment and host circulation, the airway epithelium can modulate the host response by acting either as a pro-inflammatory "sensor/amplifier" or anti-inflammatory "insulator/dampener". Airway inflammation is a two edged sword that must be precisely regulated. Thus, following pro-inflammatory stimulation, negative feedback mechanisms are typically invoked to restore homeostasis. Such adaptations are likely important in the setting of chronic microbial product exposure typical of chronic bronchitis and cystic fibrosis, but remain poorly understood. We hypothesize that adaptation is a key determinant of airway inflammation and that underlying mechanisms can be exploited as novel approaches for anti-inflammatory therapy. We show that the respiratory tract pathogen Pseudomonas aeruginosa activates the Toll-like receptor (TLR) pathway in airway epithelial cells, which become tolerant as manifest by decreased cytokine production and hypo-responsiveness to secondary stimulation. Gene array of Pseudomonas-tolerant versus -sensitive airway epithelial cells demonstrated induction of 3 prominent negative regulators of TLR signaling. To understand the role and consequences of airway epithelial adaptation, we propose the following Specific Aims: 1) To define the role of IRAKM, A20 and DUSP5 in airway epithelial tolerance to Pseudomonas aeruginosa, and 2) To determine if inhibitors of the response to Ps. a. can blunt airway inflammation in vivo without rendering the host susceptible to lung destruction or systemic dissemination of infection. To accomplish these aims, we will first test candidate tolerance-inducing genes on NF-KB- and AP-1- dependent transcription in a human airway epithelial cell line, with verification in primary well-differentiated cells. We will then determine the level of action in the signal transduction cascade and will explore inhibitory mechanisms. Finally, we will determine if manipulating tolerance-inducing genes in vivo can exploit a therapeutic window to decrease inflammation without excessively compromising host defense. A greater understanding of airway epithelial adaptation, and its functional outcome, provides a logical basis for the design of novel anti-inflammatory therapies.

描述（由申请人提供）：气道上皮在环境和宿主循环之间进行策略性插入，可以通过用作促炎的“传感器/放大器”或抗炎的“绝缘子/阻尼器”来调节宿主反应。气道炎症是一把必须精确调节的两把剑。因此，在促炎性刺激下，通常调用负反馈机制来恢复体内平衡。这种适应可能在典型的慢性支气管炎和囊性纤维化的慢性微生物产物暴露中可能很重要，但仍知之甚少。我们假设适应是气道炎症的关键决定因素，并且可以将基本机制剥削为抗炎治疗的新方法。我们表明，铜绿假单胞菌的呼吸道病原体会激活气道上皮细胞中的Toll样受体（TLR）途径，这会因细胞因子的产生降低和对二次刺激的低反应而表现为耐受性。耐假单胞菌与敏感气道上皮细胞的基因阵列表现出3个突出的TLR信号传导的显着负调节剂。为了了解气道上皮适应的作用和后果，我们提出了以下特定目的：1）定义IRAKM，A20和DUSP5在气道上皮耐受性中对铜绿假单胞菌的上皮耐受性，以及2）以确定是否对PS响应的抑制剂。一个。可以在体内钝化气道炎症，而不会使宿主容易受到肺部破坏或全身传播感染的影响。为了实现这些目标，我们将首先在人类气道上皮细胞系中对NF-KB-和AP-1依赖性转录的候选耐受性诱导基因进行测试，并在原发性良好的细胞中进行验证。然后，我们将确定信号转导级联中的作用水平，并将探索抑制机制。最后，我们将确定在体内操纵耐受性诱导基因是否可以利用治疗窗口减少炎症而不会过度损害宿主防御。对气道上皮适应及其功能结果的更多了解为设计新型抗炎疗法的设计提供了逻辑基础。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SERCA2 regulates non-CF and CF airway epithelial cell response to ozone.

DOI：
10.1371/journal.pone.0027451
发表时间：
2011
期刊：
PloS one
影响因子：
3.7
作者：
Ahmad S;Nichols DP;Strand M;Rancourt RC;Randell SH;White CW;Ahmad A
通讯作者：
Ahmad A

Hypoxia-inducible factor-1 signalling promotes goblet cell hyperplasia in airway epithelium.

DOI：
10.1002/path.2863
发表时间：
2011-06
期刊：
The Journal of pathology
影响因子：
0
作者：
Polosukhin VV;Cates JM;Lawson WE;Milstone AP;Matafonov AG;Massion PP;Lee JW;Randell SH;Blackwell TS
通讯作者：
Blackwell TS