Specialized molecules with essential roles in mucus production

在粘液产生中发挥重要作用的特殊分子

• 批准号: 8010842
• 负责人: David J Erle
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010842
• 关键词: AGR2 gene; Accounting; Affect; Allergens; Allergic; Area; Asthma; Binding; Cells; Characteristics; Chronic Obstructive Airway Disease; Cigarette Smoker; Complement; Complex; Cysteine; DNA Sequence Rearrangement; Data; Endoplasmic Reticulum; Epithelial Cells; Family; Family member; Gel; Glycoproteins; Goals; Human; Immunoprecipitation; Individual; Intestines; Investigation; Knockout Mice; Lead; Lung diseases; MUC5AC gene; MUC5B gene; Methods; Microarray Analysis; Modeling; Molecular; Morbidity - disease rate; Muc 2 protein; Mucin-2 Staining Method; Mucins; Mucous body substance; Mus; Play; Process; Production; Property; Protein Disulfide Isomerase; Proteins; Quaternary Protein Structure; Relative (related person); Residual state; Ribonucleoproteins; Role; Smoker; Specialized Epithelial Cell; Specificity; Stomach; Testing; Work; base; design; disulfide bond; in vivo; inhibitor/antagonist; member; mortality; mouse model; novel; prevent; public health relevance; secretory protein; sound; therapeutic target

DESCRIPTION (provided by applicant): Excessive mucus production is an important contributor to morbidity and mortality in common lung diseases, including asthma and COPD. We recently discovered that the protein anterior gradient homolog 2 (AGR2) plays an essential role in mucus production. AGR2 is a member of the protein disulfide isomerase (PDI) family that is found in the endoplasmic reticulum of mucus-producing cells. PDI family members assist in the folding and assembly of secreted proteins by catalyzing the rearrangement of cysteine disulfide bonds. There are 19 known mammalian PDIs but little is known about the specific roles of individual PDIs. Our data indicate that AGR2 has a specialized role in processing of mucins, the enormous cysteine-rich glycoproteins that are responsible for the characteristic viscoelastic properties of mucus. We produced Agr2-/- mice and found that these mice developed normally but were completely devoid of intestinal mucus and the major intestinal mucin MUC2. In a mouse model of asthma, production of the major airway mucin MUC5AC was reduced but not abolished in Agr2-/- mice. Preliminary studies indicate that MUC5AC is a substrate for AGR2 and for AGR3, a closely related PDI that is highly expressed in airway epithelial cells. We hypothesize that AGR3, like AGR2, plays a role in airway mucus production and that blocking expression or function of both AGR2 and AGR3 will dramatically reduce or completely prevent airway mucus production. Further studies are required to test this hypothesis and to determine whether AGR2 and AGR3 play a direct role in processing of any other proteins. We have three specific aims designed to provide a detailed understanding of the functions of AGR2 and AGR3 at the molecular, cellular, and organismal levels. In Aim 1, we will analyze AGR2 and AGR3 substrate binding specificity. In Aim 2, we will examine effects of AGR2 and AGR3-deficiency in the mouse airway. In Aim 3, we will analyze functions of AGR2 and AGR3 in human airway epithelial cells. The proposed studies will advance this novel area of investigation by providing fundamental information about the functions of AGR2 and AGR3 and by determining whether these unusual PDIs are promising therapeutic targets. PUBLIC HEALTH RELEVANCE: Excessive mucus production contributes to morbidity and mortality in common lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). We discovered a protein that is necessary for mucus production. This project will help us understand mucus production better and might lead to new treatments.

描述（由申请方提供）：粘液产生过多是常见肺部疾病（包括哮喘和COPD）发病率和死亡率的重要因素。我们最近发现，蛋白质前梯度同系物2（AGR 2）在粘液产生中起着至关重要的作用。AGR 2是蛋白质二硫键异构酶（PDI）家族的成员，其发现于粘液产生细胞的内质网中。PDI家族成员通过催化半胱氨酸二硫键的重排来帮助分泌蛋白的折叠和组装。有19种已知的哺乳动物PDI，但对个体PDI的具体作用知之甚少。我们的数据表明，AGR 2在处理粘蛋白中具有专门的作用，粘蛋白是负责粘液的特征粘弹性的巨大的富含半胱氨酸的糖蛋白。我们生产了Agr 2-/-小鼠，发现这些小鼠发育正常，但完全缺乏肠粘液和主要的肠粘蛋白MUC 2。在哮喘小鼠模型中，Agr 2-/-小鼠的主要气道粘蛋白MUC 5AC的产生减少，但没有消除。初步研究表明，MUC 5AC是AGR 2和AGR 3的底物，AGR 3是在气道上皮细胞中高度表达的密切相关的PDI。我们假设AGR 3和AGR 2一样，在气道粘液产生中起作用，阻断AGR 2和AGR 3的表达或功能将显著减少或完全阻止气道粘液产生。需要进一步的研究来验证这一假设，并确定AGR 2和AGR 3是否在任何其他蛋白质的加工中发挥直接作用。我们有三个具体的目标，旨在提供AGR 2和AGR 3在分子，细胞和生物体水平上的功能的详细了解。在目标1中，我们将分析AGR 2和AGR 3底物结合特异性。在目的2中，我们将检查AGR 2和AGR 3缺陷在小鼠气道中的作用。在目的3中，我们将分析AGR 2和AGR 3在人气道上皮细胞中的功能。拟议的研究将通过提供有关AGR 2和AGR 3功能的基本信息以及确定这些不寻常的PDI是否是有希望的治疗靶点来推进这一新的研究领域。 公共卫生关系：过多的粘液产生导致常见肺部疾病的发病率和死亡率，包括哮喘和慢性阻塞性肺病（COPD）。我们发现了一种粘液产生所必需的蛋白质。这个项目将帮助我们更好地了解粘液的产生，并可能导致新的治疗方法。