STRUCTURE AND FUNCTION OF SURFACTANT APOPROTEINS

功能性表面活性剂是正常呼吸所必需的。稀薄的血气屏障 包括肺泡表面活性剂膜的皮肤也必须保持无慢性炎症，这是每天暴露于数千升潜在污染空气的挑战。表面活性剂蛋白，最初的特点是脂质结合和生物物理活性的基础上，似乎有助于表面活性剂的体内平衡和肺的稳定性和多层肺泡免疫防御。我们的广泛目标是提供一个更机械的理解，表面活性蛋白如何执行这些双重作用和它们的相对生理意义。我们的研究最终可能与表面活性物质稳态异常直接相关的疾病有关，如急性呼吸窘迫综合征（过少）和肺泡蛋白沉积症（过多）以及慢性炎症性疾病，如BPD和COPD。我们建议测试的一般假设，特定的配体识别的离散序列和构象的表面活性剂蛋白A和D介导的双重，有时重叠的功能，表面活性剂生理和宿主防御。我们的研究设计是基于结构产生功能这一真理。我们将首先描述特定蛋白质-配体相互作用的结构基础，然后使用一系列功能实验探索这些相互作用在肺泡生理学中的作用。我们将从位点特异性蛋白质诱变和体外生物化学和细胞测定开始，并使用转基因小鼠模型进行体内研究。

A functional surfactant is critically required for normal respiration. The thin blood-gas barrier that includes the alveolar surfactant film must also be maintained free of chronic inflammation, a challenge in the face of daily exposure to thousands of liters of potentially contaminated air. The surfactant proteins, initially characterized on the basis of lipid-binding and biophysical activity, appear to contribute to both surfactant homeostasis and lung stability and a multilayered alveolar immune defense. Our broad objective is to provide a more mechanistic understanding of how the surfactant proteins perform these dual roles and their relative physiological significance. Our studies may ultimately be relevant to diseases directly linked to abnormal surfactant homeostasis such as acute respiratory distress syndromes (too little) and alveolar proteinosis (too much) as well as chronic inflammatory diseases such as BPD and COPD. We propose to test the general hypothesis that specific ligand recognition by discrete sequences and conformations of surfactant proteins A and D mediates dual and sometimes overlapping functions in surfactant physiology and host defense. Our study design is based on the truism that structure begets function. We will first characterize the structural basis of specific protein-ligand interactions and then explore the role of these interactions in alveolar physiology using a sequence of functional experiments. We will start with site-specific protein mutagenesis and in vitro biochemical and cellular assays and progress to studies in vivo using transgenic mouse models.