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: 7618492
• 负责人: Susan H. Guttentag
• 金额: $ 40.25万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618492
• 关键词: Adult; Adult Respiratory Distress Syndrome; Air; Alveolar; Area; Biogenesis; Breathing; Cell Differentiation process; Cell physiology; Cells; Chemicals; Chronic lung disease; Clara cell; Cysteine; Data; Development; Disease; Distal; Elements; Endoplasmic Reticulum; Enzymes; Event; Fetal Lung; Foundations; Functional disorder; Funding; Genetic; Human; Hyperplasia; In Vitro; Infant; Inherited; Liquid substance; Lung diseases; Mediating; Molecular; Molecular Chaperones; Pathway interactions; Pattern Recognition; Pepsinogen C; Peptide Hydrolases; Peptides; Phase; Phenylbutyrates; Phospholipids; Physiology; Play; Post-Translational Protein Processing; Post-Translational Regulation; Pregnancy; Premature Infant; Process; Production; Proteins; Proteolytic Processing; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactants; Regulation; Respiratory distress; Role; Second Pregnancy Trimester; Signal Transduction; Site; Specific qualifier value; Specificity; Structure; Structure of parenchyma of lung; Sulfhydryl Compounds; Surface; Surface Tension; System; Testing; Transcriptional Regulation; Type II Epithelial Receptor Cell; Work; alveolar lamellar body; alveolar type II cell; base; cell type; disulfide bond; extracellular; human TYRP1 protein; improved; lung development; lung maturation; monolayer; novel; novel therapeutics; polypeptide; protein protein interaction; respiratory distress syndrome; stem; success; surfactant; trafficking

DESCRIPTION (provided by applicant): Surfactant Protein B (SP-B) plays a central role in alveolar type II cell physiology. As a component of pulmonary surfactant, it facilitates transfer of phospholipids to the air-liquid interface, lowering of monolayer surface tension, and altering of monolayer composition. SP-B is critical to the differentiation of type II cells, specifically lamellar body genesis. We have been exploring the post-translational regulation of SP-B production. This stems from observations that despite increasing SP-B RNA, mature SP-B protein does not accumulate in the fetal lung until late in gestation, thereby allowing for a burst of SP-B production that facilitates LB genesis and surfactant secretion into fetal lung fluid. We have shown that post-translational events in SP-B biogenesis are important in regulating the production and transit of SP-B in the alveolar type II cell. These events are especially critical when de novo synthesis of surfactant is essential, as in the final phase of lung maturation for the transition to air breathing (as in RDS), and when extracellular and/or intracellular surfactant stores are depleted (as in ARDS). Work from the previous funding period demonstrated that enzymes involved in proSP-B post-translational processing are important to type II cell physiology. Based on new preliminary data, we hypothesize now that post-translational events involving the protease Pepsinogen C (PGC) and ER chaperones such as ERp29 are critical for regulating SP-B production, and consequently lamellar body genesis and type II cell physiology. We will test this hypothesis in 3 specific aims: 1) Characterize the role of PGC in SP-B proteolytic processing, 2) Establish key transcriptional elements directing the developmental and cell-type specificity of PGC expression, and 3) Demonstrate that chaperone interactions, specifically ERp29:proSP-B interactions, facilitate export of proSP-B from the ER. We will use an in vitro system of human type II cell differentiation to examine the process of lamellar body genesis as a result of disrupted SP-B processing/trafficking. Project Narrative: Surfactant therapy has been a success for premature infants with respiratory distress, but has not been as successful in adults. Adult respiratory distress syndrome is associated with dysfunction or decreased Surfactant Protein B (SP-B). These studies will improve our understanding of factors that control SP-B production and will provide a foundation for novel therapeutic strategies to enhance SP-B production and surfactant function.

描述(申请人提供)：表面活性蛋白B(SP-B)在肺泡II型细胞生理学中起核心作用。作为肺表面活性物质的一种成分，它促进磷脂转移到气液界面，降低单层表面张力，改变单层组成。SP-B对II型细胞的分化至关重要，尤其是板层小体的形成。我们一直在探索SP-B生产的翻译后调控。这是因为观察到，尽管SP-B RNA增加，但成熟的SP-B蛋白直到妊娠后期才在胎儿肺中积累，从而允许SP-B的突然产生，促进LB的生成和表面活性物质向胎儿肺液的分泌。我们已经证明，SP-B生物发生中的翻译后事件在调节肺泡II型细胞中SP-B的产生和转运方面是重要的。当表面活性物质的从头合成是必不可少的时，这些事件尤其关键，例如在肺成熟向空气呼吸过渡的最后阶段(如RDS)，以及当细胞外和/或细胞内表面活性物质储备耗尽时(如ARDS)。上一次资助期的研究表明，参与Prosp-B翻译后处理的酶对II型细胞生理学很重要。根据新的初步数据，我们现在假设，涉及蛋白酶胃蛋白酶原C(PGC)和ER伴侣(如ERp29)的翻译后事件对于调节SP-B的产生，从而调节板层小体发生和II型细胞生理至关重要。我们将在3个具体目标上验证这一假说：1)表征PGC在SP-B蛋白降解过程中的作用，2)建立指导PGC表达的发育和细胞类型特异性的关键转录元件，以及3)证明伴侣相互作用，特别是ERp29：ProSP-B相互作用，促进ProSP-B从内质网输出。我们将使用人类II型细胞分化的体外系统来研究由于SP-B处理/运输中断而导致的板层小体发生的过程。项目简介：表面活性物质疗法在早产儿呼吸窘迫中取得了成功，但在成人中却没有那么成功。成人呼吸窘迫综合征与功能障碍或表面活性蛋白B(SP-B)降低有关。这些研究将加深我们对控制SP-B产生的因素的理解，并将为加强SP-B产生和表面活性物质功能的新的治疗策略提供基础。