MUCIN SECRETION IN COLUMNAR EPITHELIAL CELLS

柱状上皮细胞中的粘蛋白分泌

• 批准号: 2727199
• 负责人: RAHUL P KUVER
• 金额: $ 11.96万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2727199
• 关键词: biological signal transduction; chimeric proteins; chloride channels; chloride ion; cystic fibrosis; electrical measurement; electrophysiology; epithelium; exocytosis; gallbladder; immunofluorescence technique; mucins; mucus; posttranslational modifications; secretion; tissue /cell culture

Mucins are high molecular weight glycoproteins which form a viscous gel lining epithelial surfaces forming a physical barrier between the host and the environment. All columnar epithelial cells secrete mucins, as do specialized goblet cells lining the gastrointestinal tract. A mechanistic understanding of mucin secretion has clinical relevance for a number of diseases including cystic fibrosis (CF), inflammatory bowel disease and peptic ulcer disease. Prior work on mucin secretion has been performed in neoplastic cells. Furthermore, much of the knowledge in this field is derived from the study of goblet cells. Whether the same processes apply to non-neoplastic columnar epithelial cells is not known. We propose to employ cystic fibrosis as a disease model to probe structural and functional aspects of mucin secretion in columnar epithelial cells. Thick mucus is a phenotypic hallmark and causes much of the morbidity of CF. Studies by our group and others show a complex relationship between CFTR, the chloride channel defective in CF patients, and the processes by which mucin glyproteins are secreted by columnar epithelial cells. We hypothesize that in CF columnar epithelial cells, post-translational processing of mucin glycoproteins and mucin granule exocytosis are altered. The specific aims are to: 1. Characterize the signal transduction pathways involved in mucin secretion in columnar epithelial cells, and determine whether mucin secretion is dependent on chloride ion movements. 2. Investigate mucin post-translational processing in columnar epithelial cells. 3. Determine whether CFTR is functionally involved in mucous granule exocytosis in columnar epithelial cells. 4. Determine whether isolated mucous granules contain functional CFTR This proposal will provide a structured framework of research training for the candidate. The sponsor's group's expertise in biliary cell biology will ensure a supportive and stimulating environment for the candidate.

粘蛋白是高分子量糖蛋白，它形成粘性凝胶衬里上皮表面，在宿主和环境之间形成物理屏障。 所有柱状上皮细胞都分泌粘蛋白，胃肠道内壁的特殊杯状细胞也分泌粘蛋白。 对粘蛋白分泌机制的了解与许多疾病具有临床相关性，包括囊性纤维化 (CF)、炎症性肠病和消化性溃疡病。先前已在肿瘤细胞中进行了粘蛋白分泌的研究。 此外，该领域的许多知识都源自对杯状细胞的研究。 相同的过程是否适用于非肿瘤性柱状上皮细胞尚不清楚。 我们建议采用囊性纤维化作为疾病模型来探讨柱状上皮细胞粘蛋白分泌的结构和功能方面。 浓稠的粘液是一个表型标志，也是 CF 发病的主要原因。我们小组和其他人的研究表明，CFTR（CF 患者的氯离子通道缺陷）与柱状上皮细胞分泌粘蛋白糖蛋白的过程之间存在复杂的关系。 我们假设在 CF 柱状上皮细胞中，粘蛋白糖蛋白的翻译后加工和粘蛋白颗粒胞吐作用发生了改变。 具体目标是： 1. 表征柱状上皮细胞粘蛋白分泌所涉及的信号转导途径，并确定粘蛋白分泌是否依赖于氯离子运动。 2. 研究柱状上皮细胞中粘蛋白的翻译后加工。 3.确定CFTR是否在功能上参与柱状上皮细胞的粘液颗粒胞吐作用。 4.确定分离的粘液颗粒是否含有功能性CFTR 该提案将为候选人提供一个结构化的研究培训框架。 申办者团队在胆管细胞生物学方面的专业知识将确保为候选人提供支持和刺激的环境。