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: 6824026
• 负责人: Susan H. Guttentag
• 金额: $ 36.47万
• 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/6824026
• 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

EXCEED THE SPACE PROVIDED. \ 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 Deriod 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 ¿elated to type 2 cell differentiation. SP-B deficiency is a component of the developmental lung iisease(RDS), of fatal respiratory failure from genetic deficiency (inherited SP-B deficiency), and of iiseases 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 ievelopmentally regulated and hormonally responsive at the post-translational level. It is therefore ogical that SP-B processing enzymes would have a role in human lung diseases. Characterization of ^P-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 )rotease inhibitors expand, improved understanding of the SP-B processing proteases will be accessary to evaluate new generation protease inhibitors. We therefore hypothesize that proSP-B processing requires type 2 cell specific proteases which are developmentally and hormonally ¿egulated similarly to SP-B to facilitate the coordinated expression of substrate and enzyme, "urthermore, spatial regulation of enzyme and substrate in specific subcellular organelles results in >tepwise proteolysis of proSP-B which is required for exposing trafficking signals and finally in iberating mature SP-B in the multivesicular body. The proposed studies will: 1. Determine the dentity of the N-Flanking domain of proSP-B and its role in SP-B trafficking; 2. Characterize the ievelopmental and hormonal regulation of Cathepsin H, Napsin A and Gastricsin in developing fetal ung; and 3. Establish the roles of Cathepsin H, Napsin A and Gastricsin in proSP-B processing. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。SP-B在2型细胞中功能性表面活性剂系统的发展中的中心作用得到了遗传性SP-B缺陷的公开描述、先前资助Deriod关于SP-B加工的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缺乏是发育性肺疾病（RDS）、遗传性SP-B缺乏引起的致命性呼吸衰竭（遗传性SP-B缺乏）以及成人和儿童的表面活性物质功能障碍（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。我们的研究表明，SP-B的表达在翻译后水平上受到发育调节和免疫应答。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。对SP-B加工酶的表征将为制备用于外源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rotease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有助于评估新一代蛋白酶抑制剂。因此，我们假设proSP-B的加工需要2型细胞特异性蛋白酶，这些蛋白酶在发育和发育过程中起作用。类似于SP-B进行调节以促进底物和酶，“尿苷酸，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分离成熟SP所必需的。多泡体中的B。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。性能现场=