MECHANISMS OF SURFACTANT INHIBITION

表面活性剂抑制机制

• 批准号: 6696344
• 负责人: FRANCISKUS JOHANNES WALTHER
• 金额: $ 29.28万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696344
• 关键词: disease /disorder model; hydropathy; inhibitor /antagonist; intermolecular interaction; laboratory rabbit; laboratory rat; newborn animals; peptide chemical synthesis; phospholipids; protein structure function; pulmonary surfactants; respiratory distress syndrome of newborn; respiratory gas level; surface property; synthetic peptide

DESCRIPTION (Applicant's Abstract): Lung surfactant is a surface-active material that lines the alveolar surface of the lung and is composed of -90 percent lipids and 5-10 percent surfactant proteins (SF-A, B, C, and D). SF-A and SP-D are complex, lung-specific glycoproteins which modulate surfactant metabolism and lung immunological defense. SP-B and SP-C are short hydrophobic proteins, responsible for the surface activity of clinical surfactants derived from bovine and porcine lungs. Because natural surfactant preparations vary considerably in protein composition and may expose recipients to immunogenic proteins and viral contamination, we have focused on the structural and functional characteristics of synthetic mimics of human SP-B and SP-C and the design of a standardized, reproducible surfactant preparation of controlled composition. Premature infants with respiratory distress syndrome (RDS) are surfactant deficient due to lung immaturity, but functional surfactant deficiency due to inhibition of lung surfactant in the alveolar space predominates in adult respiratory distress syndrome (ARDS). Our objective is to design synthetic surfactants that will resist various types of inhibition associated with ARDS. The proposed studies include the design, synthesis, structural characterization, and in vitro and in vivo surface activity testing of synthetic lung surfactant formulations composed of phospholipids and SP-B and SP-C mimic peptides for use in the treatment of lung surfactant deficiency, surfactant inhibition, and bacterial pneumonia. We propose to extend these synthetic peptide design efforts to the synthesis of disulfide linked SP-B and SF-C homodimers that are similar to native hydrophobic surfactant proteins. Since SP-B and SF-C interact in vitro and in vivo and SP-A decreases the inhibition sensitivity of surfactant preparations, we will assess the surface activity of formulations with synthetic SF-B and SP-C mimic peptides and native SF-A. Overall, these studies will facilitate the identification and development of novel, peptide containing lung surfactant formulations that should be useful for treating surfactant deficiency and surfactant inhibition in neonatal RDS and ARDS.

描述（申请人的摘要）：肺表面活性剂是一种表面活性 将肺肺泡表面排成并由-90组成的材料 脂质百分比和5-10％的表面活性剂蛋白（SF-A，B，C和D）。 SF-A SP-D是复杂的，肺特异性的糖蛋白，可调节表面活性剂 代谢和肺免疫辩护。 SP-B和SP-C是短疏水 蛋白质，负责衍生的临床表面活性剂的表面活性 来自牛和猪肺。因为天然表面活性剂制剂有所不同 在蛋白质成分中相当大，可能使受体暴露于免疫原性 蛋白质和病毒污染，我们专注于结构和 人类SP-B和SP-C合成模拟的功能特征以及 设计的标准化，可再现的表面活性剂制备受控的 作品。呼吸窘迫综合征（RDS）的早产儿是 表面活性剂由于肺不成熟而缺乏，但功能性表面活性剂 由于肺泡空间中肺表面活性剂的抑制作用而缺乏 成人呼吸窘迫综合征（ARDS）主要是。我们的目标是 设计合成表面活性剂将抵抗各种类型的抑制作用 与ARDS相关。拟议的研究包括设计，合成， 结构表征，体外和体内表面活性测试 由磷脂和SP-B组成的合成肺表面活性剂制剂 和SP-C模拟肽用于治疗肺表面活性剂缺乏症， 表面活性剂抑制和细菌性肺炎。我们建议扩展这些 合成肽设计工作，用于合成二硫键链接的SP-B和 类似于天然疏水表面活性剂蛋白的SF-C同型二聚体。 由于SP-B和SF-C在体外以及体内和SP-A相互作用降低 表面活性剂制剂的抑制敏感性，我们将评估表面 合成SF-B和SP-C模拟肽和天然的配方活性 SF-A。总体而言，这些研究将促进识别和发展 新颖的，含有肺表面活性剂制剂的肽 用于治疗新生儿RD的表面活性剂缺乏和表面活性剂抑制 和ards。