MECHANISMS OF SURFACTANT INHIBITION

表面活性剂抑制机制

• 批准号: 2332553
• 负责人: FRANCISKUS JOHANNES WALTHER
• 金额: $ 22.15万
• 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 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2332553
• 关键词: adsorption; circular dichroism; disease /disorder model; electron spin resonance spectroscopy; fluorescent dye /probe; infrared spectrometry; inhibitor /antagonist; interferometry; intermolecular interaction; laboratory rabbit; laboratory rat; monoclonal antibody; peptide chemical synthesis; peptide library; pulmonary surfactants; respiratory distress syndrome of newborn; respiratory gas level; serum albumin; surface property; synthetic peptide

Key surfactant protein functions, such as lipid mixing, adsorption, and dynamic compression, that are associated with amphipathic domains are probably the most affected by surfactant inhibitors. Based on the known amino acid sequences of the surfactant proteins SP-A, SP-B, and SP-C, we will synthesize a family of peptides for use in characterizing the interactions of synthetic surfactant dispersions with surfactant inhibitors. These peptides will include short length, functional domains (eg. amphipathic and transmembrane sequences) of SP-A, SP-B, SP-C and full-length proteins representing SP-B (78 residues) and SP-C (35 residues). To evaluate the inhibitory actions of serum components such as serum albumin and anti-surfactant protein antibodies, synthetic peptides will be tested for their in vitro surface activity with and without inhibitors. Surfactant inhibitors will also be investigated for their effects on the mixing function of the surfactant dispersions using fluorescence vesicle assays. These studies will allow a better understanding of which surfactant protein functions (i.e., adsorption, spreading, dynamic compression and respreading, lipid mixing) are perturbed by inhibitors. With the information derived from these in vitro tests of surfactant inhibition, we will assess the interactions between surfactant peptides and inhibitors using physical-biochemical techniques, such as circular dichroism (CD), Fourier transform infrared (FTIR) and electron spin resonance (ESR) spectroscopy, to evaluate whether protein inhibitors (e.g., albumin, anti-surfactant protein antibodies) block surfactant activity by interacting with the amphipathic, surface-seeking domains of surfactant proteins. Finally, the effectiveness of synthetic peptide-lipid mixtures, with and without inhibitor proteins, in restoring lung function will be tested in two animal models of surfactant deficiency and inactivation. These experiments should provide information on dose-response relationships of synthetic surfactant preparations in vivo and identify those conditions under which the in vitro findings of the inhibitor studies predict the in vivo function of synthetic surfactants. This information may not only help in determining component(s) of a surfactant dispersion resist inhibitors, but also in designing synthetic surfactants that offer resistance against inhibition in the respiratory distress syndrome.

关键的表面活性蛋白质功能，如脂质混合、吸附和 与两亲性结构域相关的动态压缩是 可能是受表面活性物质抑制剂影响最大的。基于已知的 表面活性蛋白SP-A、SP-B和SP-C的氨基酸序列 将合成一系列多肽用于表征 合成表面活性剂分散体与表面活性剂的相互作用 抑制剂。这些多肽将包括短长度的功能结构域 (例如，SP-A、SP-B、SP-C和 代表SP-B(78个残基)和SP-C(35个残基)的全长蛋白质 残留物)。为了评价血清成分的抑制作用 作为血清白蛋白和抗表面活性蛋白抗体，合成 将用和测试多肽的体外表面活性。 没有抑制剂的话。表面活性物质的抑制剂也将被研究 它们对表面活性剂分散体混合性能的影响 荧光小泡分析。这些研究将允许更好的 了解哪些表面活性剂蛋白质起作用(即，吸附， 铺展、动态压缩和再铺展、脂质混合)是 被抑制剂扰乱的。从这些体外实验中获得的信息 表面活性剂抑制试验，我们将评估两者之间的相互作用 使用物理-生化技术的表面活性多肽和抑制剂， 例如圆二向色性(CD)、傅里叶变换红外(FTIR)和 电子自旋共振(ESR)波谱，以评估蛋白质 抑制物(如白蛋白、抗表面活性蛋白抗体)阻断 表面活性通过与两亲性、表面寻求性相互作用 表面活性蛋白质的结构域。最后，综合评价了综合治理的有效性。 含和不含抑制蛋白的多肽-脂质混合物在修复中的作用 肺功能将在两种表面活性物质的动物模型中进行测试 缺乏和失活。这些实验应该提供信息 人工合成表面活性剂制剂的剂量-反应关系 并确定在哪些条件下体外发现的 抑制剂研究预测人工合成的体内功能 表面活性剂。这些信息不仅有助于确定 成分(S)是一种表面活性剂分散抗蚀剂，也在 设计具有抗抑制性的合成表面活性剂 呼吸窘迫综合症。