Therapeutic Surfactants

 描述（由申请人提供）：本提案旨在建立开发治疗性表面活性剂的新方法。肺表面活性剂降低肺部的表面张力。在没有功能性表面活性剂的情况下，呼吸会破坏分隔肺泡ai和毛细肺的薄屏障。在肺表面活性物质充足之前出生的早产儿中，使用从动物来源获得的外源性表面活性物质治疗显著提高了存活率。然而，这些药物还没有足够的量用于治疗患有也可能涉及异常表面活性剂的疾病的成年人。拟议的研究旨在为设计可用于成人的廉价表面活性剂提供基础。这两个具体目标对这一问题采取了不同的办法。第一个目标是解决疏水表面活性剂蛋白SP-B促进表面活性剂脂质形成界面膜的机制。快速吸附是肺表面活性物质降低表面张力必须完成的第一步。模拟SP-B这种功能的因素可以为设计人工表面活性剂提供基础。我们的初步结果表明，模型中的蛋白质稳定的限速动力学中间体。这种假设结构的脂质将形成从吸附囊泡延伸到空气/液体的柄 接口.茎中的每个小叶将具有负曲率，由亲水面的凹形形状限定。实验将使用X射线散射来确定SP-B是否可以通过诱导更多的负曲率或通过使瓣叶更灵活来减少形成这种结构所需的弯曲能量。X射线散射还将定位脂质内的蛋白质，以确定它们如何实现其结构和功能效应。第二个目标将改为使用天然表面活性剂不可用的促进吸附的机制。我们的初步结果表明，如何准备可能实现快速吸附替代机制的模型。目的是测试模型在实验中产生的假设，这些实验将通过磷核磁共振和X射线散射建立的结构与捕获气泡和切除肺获得的功能相关联。

 DESCRIPTION (provided by applicant): This proposal seeks to establish new methods for developing therapeutic surfactants. Pulmonary surfactant lowers surface tension in the lungs. In the absence of functional surfactant, breathing injures the thin barrier that separates alveolar ai from capillary lungs. In premature babies born before the lungs have adequate amounts of pulmonary surfactant, treatment with exogenous surfactants obtained from animal sources has significantly improved survival. These agents, however, have been unavailable in sufficient quantities for treatment of adults with disorders that also may involve abnormal surfactant. The proposed studies seek to provide the basis for designing inexpensive surfactants that could be used in adults. The two specific aims take different approaches to this problem. The first aim addresses the mechanisms by which the hydrophobic surfactant protein SP-B promotes the surfactant lipids to form an interfacial film. Rapid adsorption is the first step that pulmonary surfactant must accomplish to reduce surface tension. Factors that mimic this function of SP-B could then provide the basis for designing artificial surfactants. Our preliminary results suggest model in which the protein stabilizes a rate-limiting kinetic intermediate. The lipids of this hypothetical structure would form a stalk that extends from the adsorbing vesicle to the air/liquid interface. Each of the leaflets in the stalk would have negative curvature, defined by the concave shape of the hydrophilic face. Experiments will use X-ray scattering to determine if SP-B can make changes that would reduce the energy of bending required to form this structure, either by inducing more negative curvature or by making the leaflets more flexible. X- ray scattering will also locate the protein within the lipids to determine how they accomplish their structural and functional effects. The second aim will instead use mechanisms for promoting adsorption that are unavailable to native surfactant. Our preliminary results suggest a model for how preparations might achieve rapid adsorption by alternative mechanisms. The aim tests hypotheses generated by the model in experiments that correlate structures established by phosphorus-nuclear magnetic resonance and X-ray scattering with function obtained with both captive bubbles and excised lungs.