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的物理性质方面起着关键作用。肺表面活性物质蛋白B(SP-B)表达缺失是致命的，外源性肺表面活性物质的应用对某些呼吸窘迫综合征的治疗是有益的。然而，各种肺表面活性物质制剂治疗特定个体的成败是不可预测的，对SP-B在肺表面活性物质中作用的分子基础缺乏坚实的了解。了解SP-B与肺表面活性物质中存在的脂质之间的复杂相互作用，可以指导临床上针对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)和胎粪吸入等特定疾病的表面活性物质制剂的制定。确定SP-B的较小多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。我们建议研究SP-B在生理相关条件下的功能，并确定SP-B的N-端和C-端的多肽类似物是否可以与类脂形成稳定的络合物，从而模拟亲本蛋白的作用。研究这些多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复杂脂质环境中低浓度的这些参数。

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.