SURFACTANT PROTEIN

本建议是基于我们最近发现的表面活性剂蛋白B（SP-B）具有抗菌活性。 这一发现的意义有三方面。 首先，SP-B是哺乳动物肺天然的（仅在肺中表达），并由支气管、细支气管和肺泡上皮细胞以相对高的浓度分泌。 因此，它可以作为先天免疫的一个组成部分，以防止细菌定植在人类肺部。 第二，表面活性物质替代制剂窘迫综合征（NRDS和ARDS）。 研究表明，使用这种制剂不会引起免疫反应。 第三，SP-B很容易从各种物种的肺中分离和纯化。 使用SP-B来预防或根除细菌生长在诸如囊性纤维化和细菌性肺炎的疾病中尤其重要，其中发病机制可能是细菌定植和感染的结果。 我们现在将确定影响SP-B抗菌活性的因素，并将测试SP-B是先天免疫系统的一个组成部分的假设，防止非病变肺部的细菌定植，但这种活性可能会在囊性纤维化患者的肺部受损。 我们将确定SP-B杀死细菌的机制，使用定点诱变，肽合成沿着和结构/功能分析。 最后，我们将检验天然SP-B、重组SP-B和/pr SP-B合成类似物可用作体内抗菌剂的假设。

The present proposal is based on our recent discovery that Surfactant Protein B (SP-B) exhibits anti-baterial activity. The significance of this finding is three-fold. First SP-B is native to the mammalian lung (expressed solely in the lung) and is secreted by bronchial, bronchiolar and alveolar epithelial cells at relatively high concentrations. Thus, it may act as a component of innate immunity to prevent bacterial colonization in the human lung. Second, surfactant replacement preparations distress syndromes (NRDS and ARDS). Studies have shown that use of such preparations do not elicit immunological responses. Third, SP-B is easily isolated and purified from lungs of a variety of species. Use of SP-B to prevent or eradicated bacterial growth would be of especially importance in diseases such as cystic fibrosis and bacterial pneumonia, where pathogenesis is likely to be a result of bacterial colonization and infection. We will now determine the factors that affect antibacterial activity of SP-B and will test the hypothesis that SP-B is a component of the innate immune system, protecting against bacterial colonization in nondiseased lungs, but this activity may be compromised in lungs of cystic fibrosis patients. We will determine the mechanism by which SP-B kills bacteria using site-directed mutagenesis, peptide synthesis along and structural/functional analysis. Finally, we will test the hypothesis that native SP-B, recombinant SP-B and/pr SP-B synthetic analogs can be used as antibacterial agents in vivo.