Structure-Function Relationships in Lung Surfactants

描述（由申请人提供）：蛋白质在赋予哺乳动物肺表面活性物质独特物理性质方面发挥关键作用。不能表达功能性表面活性蛋白B，SP-B，是致命的，外源性肺表面活性物质的应用已被证明有益于治疗一些呼吸窘迫综合征。然而，各种肺表面活性物质制剂在治疗特定个体中的成功或失败是不可预测的，并且缺乏对SP-B在肺表面活性物质中作用的分子基础的深入理解。了解SP-B和肺表面活性物质中脂质之间的复杂相互作用可以指导临床表面活性物质制剂的配制，用于特定疾病，包括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。确定SP-B的较小肽类似物的结构和作用机制将有助于开发可替代动物源性制剂的低成本合成替代疗法。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-和C-末端的肽类似物是否可以采用与脂质的稳定复合物，其模拟亲本蛋白的作用。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。我们将使用新型、灵敏的固态核磁共振实验，使我们能够以原子分辨率确定复杂脂质环境中低浓度下的这些参数。

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.