Molecular Signals for Trafficking Surfactant Protein B

贩运表面活性剂蛋白 B 的分子信号

• 批准号: 6541760
• 负责人: Susan H. Guttentag
• 金额: $ 38.18万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6541760
• 关键词: aspartic endopeptidases; biological signal transduction; clinical research; cysteine endopeptidases; endopeptidases; enzyme substrate; hormone regulation /control mechanism; human tissue; organ culture; protein biosynthesis; proteolipids; proteolysis; pulmonary surfactants; respiratory epithelium

DESCRIPTION (provided by applicant): A central role for SP-B in the development of a functional surfactant system in type 2 cells is supported by published descriptions of inherited SP-B deficiency, work from the previous funding period regarding ontogeny of SP-B processing, and our preliminary data using SP-B antisense. SP-B expression and processing are integral components of type 2 cell phenotype and are intimately related to type 2 cell differentiation. SP-B deficiency is a component of the developmental lung disease (RDS), of fatal respiratory failure from genetic deficiency (inherited SP-B deficiency), and of diseases of surfactant dysfunction in adults and children (ARDS). Although the final common pathway often includes a reduction of mature SP-B in alveolar surfactant resulting in abnormal surface tension, the mechanisms are diverse. We have shown that SP-B expression is developmentally regulated and hormonally responsive at the post-translational level. It is therefore logical that SP-B processing enzymes would have a role in human lung diseases. Characterization of SP-B processing enzymes will open new avenues into preparing recombinant mature SP-B for exogenous surfactant, thus providing a more physiologic formulation. Also, as therapeutic uses of protease inhibitors expand, improved understanding of the SP-B processing proteases will be necessary to evaluate new generation protease inhibitors. We therefore hypothesize that proSP-B processing requires type 2 cell specific proteases which are developmentally and hormonally regulated similarly to SP-B to facilitate the coordinated expression of substrate and enzyme. Furthermore, spatial regulation of enzyme and substrate in specific subcellular organelles results in stepwise proteolysis of proSP-B which is required for exposing trafficking signals and finally in liberating mature SP-B in the multivesicular body. The proposed studies will: 1. Determine the identity of the N-Flanking domain of proSP-B and its role in SP-B trafficking; 2. Characterize the developmental and hormonal regulation of Cathepsin H, Napsin A and Gastricsin in developing fetal lung: and 3. Establish the roles of Cathepsin H, Napsin A and Gastricsin in proSP-B processing

描述（由申请人提供）：SP-B在2型细胞中功能性表面活性剂系统开发中的核心作用得到了遗传性SP-B缺陷的已发表描述、先前资助期关于SP-B加工个体发生的工作以及我们使用SP-B反义的初步数据的支持。SP-B的表达和加工是2型细胞表型的组成部分，与2型细胞分化密切相关。SP-B缺乏是发育性肺病（RDS）、遗传性缺乏引起的致命性呼吸衰竭（遗传性SP-B缺乏）以及成人和儿童表面活性物质功能障碍疾病（ARDS）的组成部分。虽然最终的共同途径往往包括肺泡表面活性物质中成熟SP-B的减少，导致表面张力异常，但其机制是多种多样的。我们已经表明，SP-B的表达是发育调节和翻译后水平的免疫反应。因此，SP-B加工酶在人类肺部疾病中发挥作用是合乎逻辑的。SP-B加工酶的特性将为制备外源性表面活性剂的重组成熟SP-B开辟新的途径，从而提供更具生理性的制剂。此外，随着蛋白酶抑制剂的治疗用途的扩大，对SP-B加工蛋白酶的更好理解将是评估新一代蛋白酶抑制剂所必需的。因此，我们假设proSP-B加工需要2型细胞特异性蛋白酶，这些蛋白酶与SP-B类似地在发育和生殖过程中受到调节，以促进底物和酶的协调表达。此外，酶和底物在特定亚细胞器中的空间调节导致proSP-B的逐步蛋白水解，这是暴露运输信号和最终在多泡体中释放成熟SP-B所需的。拟议的研究将：1。确定proSP-B的N-侧翼结构域的身份及其在SP-B运输中的作用; 2.表征组织蛋白酶H、Napsin A和胃泌素在发育胎肺中的发育和激素调节;以及3.确定组织蛋白酶H、Napsin A和胃泌素在proSP-B加工中的作用