ROLE OF SURFACTANT PROTEIN D IN SURFACTANT HOMEOSTASIS

表面活性蛋白 D 在表面活性剂稳态中的作用

• 批准号: 2898935
• 负责人: MACHIKO IKEGAMI
• 金额: $ 32.28万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2898935
• 关键词: alveolar macrophages; gene targeting; genetically modified animals; intermolecular interaction; laboratory mouse; lectin; lipid metabolism; phospholipids; protein structure function; pulmonary surfactants

This is an application for five years of support to study the molecular mechanisms by which SP-D, a member of the collectin family of calcium-dependent lectins, plays a critical role in surfactant phospholipid homeostasis. In the healthy lung, alveolar and tissue surfactant pool sizes are tightly regulated, however, the precise molecular mechanisms mediating surfactant homeostasis remain poorly clarified. Targeted deletion of SP-D in transgenic mice, SP-D (-/-), resulted in a marked increase in alveolar and tissue surfactant phospholipid. In SP-D (-/-) mice, the increased surfactant phospholipid was not associated with Increased surfactant proteins, but was associated with alterations in the size and appearance of alveolar macrophages, decreased tubular myelin and abnormally dense lipid forms In the alveoli. The SP-D gene targeting experiments have identified a previously unknown pathway by which the surfactant phospholipid pool sizes are selectively regulated. We will determine the ontogenesis of changes In Sat PC pool size in SP-D (+/+) and SP-D (-/-) mice and characterize surfactant phospholipid synthesis, secretion, and clearance In SP-D (-/-) mice relative to SP-D (+1+) mice. We also will answer the following questions: 1) Whether SP-D directly alters surfactant lipid structures in the airspaces, in turn, altering surfactant function and catabolism; 2) Whether SP-D interacts directly with type II cells and alveolar macrophages to signal cellular events which influence surfactant lipid uptake, catabolism, or recycling; and 3) Whether the effects of SP-D on surfactant phospholipid metabolism are mediated by specific structural domains within the SP-D molecule. The goal is to understand the role of SP-D in the cellular and/or structural mechanisms involved in independent regulation of phospholipid and surfactant protein homeostasis.

这是一个五年支持的应用，以研究分子机制，通过该分子机制，依赖钙依赖性凝集素家族的sp-d在表面活性剂磷脂稳态中起着至关重要的作用。 在健康的肺中，严格调节肺泡和组织表面活性剂池的大小，但是，介导表面活性剂稳态的精确分子机制仍然很差。 在转基因小鼠SP-D（ - / - ）中，SP-D的靶向缺失导致牙槽和组织表面活性剂磷脂的显着增加。 在SP-D（ - / - ）小鼠中，增加的表面活性剂磷脂与表面活性剂蛋白的增加无关，而与肺泡巨噬细胞的大小和外观发生变化有关，管状髓磷脂降低和肺泡中的脂质形式异常。 SP-D基因靶向实验已经确定了以前未知的途径，通过该途径，表面活性剂磷脂池的大小被选择性地调节。我们将确定SP-D（+/+）和SP-D（ - / - ）小鼠中SAT PC池大小变化的个体发生，并表征相对于SP-D（ - / - ）小鼠的表面活性剂磷脂合成，分泌和清除率。 我们还将回答以下问题：1）SP-D是否直接改变空域中的表面活性剂脂质结构，从而改变表面活性剂功能和分解代谢； 2）SP-D是否与II型细胞和肺泡巨噬细胞直接相互作用，以信号会影响表面活性剂脂质摄取，分解代谢或回收利用的细胞事件； 3）SP-D对表面活性剂磷脂代谢的影响是否是由SP-D分子内的特定结构结构域介导的。 目的是了解SP-D在磷脂和表面活性剂蛋白稳态的独立调节中涉及的细胞和/或结构机制中的作用。