Structure-Function Relationships in Lung Surfactants

肺表面活性剂的结构-功能关系

• 批准号: 6867644
• 负责人: Joanna R Long
• 金额: $ 28.78万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-07 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867644
• 关键词: calorimetry; fluorescence resonance energy transfer; fluorimetry; infrared spectrometry; lipid bilayer membrane; membrane activity; membrane proteins; membrane structure; molecular dynamics; nuclear magnetic resonance spectroscopy; peptide analog; peptide chemical synthesis; physical model; polymerase chain reaction; protein protein interaction; protein sequence; protein structure function; pulmonary surfactants

DESCRIPTION (provided by applicant): Proteins play critical roles in imparting the unique physical properties in mammalian lung surfactant. Failure to express functional surfactant protein B, SP-B, is lethal, and application of exogenous lung surfactant has proved beneficial in treating some respiratory distress syndromes. However, success or failure of various lung surfactant preparations in treating specific individuals is unpredictable, and a solid understanding of the molecular basis for the role of SP-B in lung surfactant is lacking. Understanding the complex interactions between SP-B and the lipids present in lung surfactant could direct the formulation of clinical surfactant preparations for specific diseases including adult respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), respiratory distress syndrome (RDS) in premature infants, and meconium aspiration. Determining the structure and mechanisms of action for smaller peptide analogs of SP-B would aid in the development of low-cost, synthetic replacement therapies which could replace animal-derived formulations. We propose to study the function of SP-B under physiologically relevant conditions and to determine whether peptide analogs of the N- and C- terminus of SP-B can adopt stable complexes with lipids which mimic the actions of the parent protein. Studying the structure, orientation, and locations of these peptides in bilayer membranes will aid in determining under what conditions they can serve as replacements for the full protein. We will be using novel, sensitive solid state NMR experiments which allow us to determine at atomic resolution these parameters at low concentrations in complex lipid environments.

描述（由申请人提供）：蛋白质在赋予哺乳动物肺表面活性剂独特的物理性质中起关键作用。不能表达功能性表面活性物质蛋白B （SP-B）是致命的，外源性肺表面活性物质的应用已被证明对治疗一些呼吸窘迫综合征有益。然而，各种肺表面活性物质制剂治疗特定个体的成功或失败是不可预测的，并且对SP-B在肺表面活性物质中的作用的分子基础缺乏扎实的了解。了解SP-B与肺表面活性物质中脂质之间的复杂相互作用，可以指导表面活性物质制剂的配方，用于成人呼吸窘迫综合征（ARDS）、严重急性呼吸综合征（SARS）、早产儿呼吸窘迫综合征（RDS）和胎粪吸入等特殊疾病的临床治疗。确定SP-B的小肽类似物的结构和作用机制将有助于开发低成本的合成替代疗法，以取代动物来源的配方。我们建议在生理相关条件下研究SP-B的功能，并确定SP-B的N端和C端肽类似物是否能与脂质形成稳定的复合物，从而模拟母体蛋白的作用。研究这些肽在双层膜中的结构、取向和位置将有助于确定在什么条件下它们可以作为完整蛋白质的替代品。我们将使用新颖，灵敏的固态核磁共振实验，使我们能够在原子分辨率下确定这些参数在复杂的脂质环境中的低浓度。