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Epithelial PLUNC as a determinant of Airway Mucosal Antimicrobial Activity

上皮 PLUNC 作为气道粘膜抗菌活性的决定因素

基本信息

批准号：
8316177
负责人：
Yuanpu Peter Di
金额：
$ 39.3万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8316177
关键词：
Amino Acid Motifs Anti-Bacterial Agents Antibiotic Resistance Bacteria Bacterial Infections Biotechnology Bronchitis Carcinoma Cell surface Cells Chronic lung disease Clinical Duct (organ) structure Endotoxins Epithelial Epithelial Cells Epithelium Genes Gland Gram-Negative Bacteria HIV Health Host Defense Host Defense Mechanism Human Immune response Immune system In Vitro Incidence Individual Infection Infectious Lung Disorder Intensive Care Units Invaded Knowledge Lactoferrin Leukocytes Liquid substance Lung Lung diseases Maps Mediating Messenger RNA Microarray Analysis Morphology Muramidase Mus Names Nasal Epithelium Natural Immunity Nosocomial Infections Palate Patients Peptides Predisposition Protease Inhibitor Proteins Pseudomonas Pseudomonas aeruginosa Public Health Recombinants Respiratory Tract Infections Secretory Cell Serous Sinusitis Site Specificity Structure-Activity Relationship Terminology Testing Transgenic Mice Tretinoin United States Upper respiratory tract aerosolized airway epithelium alternative treatment antimicrobial antimicrobial drug bactericidal permeability increasing protein base cDNA Arrays cystic fibrosis patients efficacy testing extracellular in vitro activity in vivo killings microbial mucoid neutralizing antibody neutrophil novel pathogen programs prophylactic protein aminoacid sequence respiratory secretory protein small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Respiratory infection is the most common lung disease with an estimated incidence of over one billion cases annually in the United States. Gram negative bacteria, particular Pseudomonas aeruginosa, are opportunistic pathogens that frequently cause hospital-acquired infections especially in ventilated patients and are the second most common infection in Intensive Care Units. The conducting airway serves as a first line of defense against bacterial insults through passive action as a barrier as well as through active contribution to antimicrobial activity of the extracellular lining fluid. Importantly, airway epithelial cell-derived proteins contribute to this milieu and promote an appropriate host defense against invading pathogens. Our long-term objective is to advance the understanding of the respiratory innate immune response especially with regard to epithelial cell-specific antimicrobial function. One molecule we believe to be critical to epithelially initiated antimicrobial defense is PLUNC (palate, lung and nasal epithelium carcinoma associated) which we co-discovered and originally named SPURT (secretory protein in upper respiratory tract). We characterized PLUNC as airway lining fluid protein that was secreted apically in primary human airway epithelial cultures and whose abundance was elevated in multiple chronic lung diseases. We demonstrated that PLUNC mRNA and protein in normal subjects were restricted to serous cells of secretory ducts and submucosal glands, sites that express high levels of other host defense proteins such as lysozyme and lactoferrin. PLUNC is abundant in airway fluid of normal individuals and our preliminary results demonstrate that it possess antimicrobial activity against P. aeruginosa. In this study, we hypothesize that mucosal PLUNC acts as an antimicrobial protein that is a critical determinant in host defense against Gram-negative bacteria. To test this hypothesis, we will pursue three specific aims. For Aim 1, the specificity of PLUNC toward common airway pathogens will be assessed and necessity of PLUNC for anti-microbial activity evaluated in vivo and in vitro. For Aim 2, PLUNC transgenic mice and prophylactic administration of recombinant PLUNC will be used to determine if elevated epithelial PLUNC protects against respiratory microbial infection. For Aim 3, the peptide sequences and protein motifs of PLUNC critical to its antimicrobial function will be mapped and utility or these peptides as endogenously generated antimicrobial agents tested. PUBLIC HEALTH RELEVANCE. Relevance to Public Health Concerns: These studies will assess innate mechanisms regulating antimicrobial activity of the airway lining fluid. By focusing on an epithelially-derived protein product, PLUNC, our study may provide an alternative treatment for respiratory infection through augmentation of native host defense mechanisms.

描述(申请人提供)：呼吸道感染是最常见的肺部疾病，估计在美国每年的发病率超过10亿例。革兰氏阴性菌，特别是铜绿假单胞菌，是一种机会致病菌，经常导致医院感染，特别是在呼吸机患者中，是重症监护病房第二常见的感染。通过作为屏障的被动作用以及通过对细胞外衬里液体的抗微生物活性的主动贡献，传导气道作为抵御细菌伤害的第一道防线。重要的是，呼吸道上皮细胞衍生蛋白有助于这种环境，并促进适当的宿主防御入侵病原体。我们的长期目标是促进对呼吸道先天免疫反应的了解，特别是关于上皮细胞特异性抗菌功能。我们认为对上皮性抗菌防御至关重要的一个分子是PLUNC(与腭部、肺癌和鼻部上皮癌相关)，我们与人共同发现并最初将其命名为SPURT(上呼吸道分泌蛋白)。我们的特征是PLUNC是一种在原代人类呼吸道上皮细胞培养中顶端分泌的呼吸道衬里液体蛋白，其丰度在多种慢性肺部疾病中升高。我们证明了正常人PLUNC的mRNA和蛋白仅限于分泌导管和粘膜下腺的浆液细胞，这些部位表达高水平的其他宿主防御蛋白，如溶菌酶和乳铁蛋白。PLUNC在正常人的气道液中含量丰富，我们的初步结果表明，它对铜绿假单胞菌具有抗菌活性。在这项研究中，我们假设粘膜PLUNC作为一种抗菌蛋白，是宿主防御革兰氏阴性菌的关键决定因素。为了验证这一假设，我们将追求三个具体目标。对于目标1，将评估PLUNC对常见呼吸道病原体的特异性，并评估PLUNC在体内和体外抗微生物活性的必要性。对于目标2，将使用PLUNC转基因小鼠和预防性给予重组PLUNC来确定升高的上皮PLUNC是否对呼吸道微生物感染具有保护作用。对于目标3，将绘制对其抗菌功能至关重要的PLUNC的多肽序列和蛋白质基序，并测试这些多肽作为内源性抗菌剂的实用性。与公共卫生相关。与公共卫生问题相关：这些研究将评估调节呼吸道衬里液体的抗微生物活性的内在机制。通过专注于上皮源性蛋白产物PLUNC，我们的研究可能通过加强本地宿主防御机制为呼吸道感染提供一种替代治疗方法。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Antimicrobial Peptides: A Potential Therapeutic Option for Surgical Site Infections.

抗菌肽：手术部位感染的潜在治疗选择。

DOI：
发表时间：
2017
期刊：
Clinics in surgery
影响因子：
0
作者：
Deslouches,Berthony;Di,YPeter
通讯作者：
Di,YPeter

K-ras mutations in lung tumors from NNK-treated mice with lipopolysaccharide-elicited lung inflammation.

DOI：
发表时间：
2011-09
期刊：
Anticancer research
影响因子：
2
作者：
P. Keohavong;B. Kahkonen;Edwina Kinchington;Jinling Yin;Jide Jin;Xiaoping Liu;J. Siegfried;DI Y.PETER
通讯作者：
P. Keohavong;B. Kahkonen;Edwina Kinchington;Jinling Yin;Jide Jin;Xiaoping Liu;J. Siegfried;DI Y.PETER

Enhanced efficacy of the engineered antimicrobial peptide WLBU2 via direct airway delivery in a murine model of Pseudomonas aeruginosa pneumonia.

DOI：
10.1016/j.cmi.2017.08.029
发表时间：
2018-05
期刊：
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases
影响因子：
0
作者：
Chen C;Deslouches B;Montelaro RC;Di YP
通讯作者：
Di YP

Inhibition of nuclear factor-erythroid 2-related factor (Nrf2) by caveolin-1 promotes stress-induced premature senescence.

DOI：
10.1091/mbc.e12-09-0666
发表时间：
2013-06
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Volonte D;Liu Z;Musille PM;Stoppani E;Wakabayashi N;Di YP;Lisanti MP;Kensler TW;Galbiati F
通讯作者：
Galbiati F

Repression of CC16 by cigarette smoke (CS) exposure.

通过香烟烟雾（CS）暴露对CC16的抑制。