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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063329-01
Application #
2898935
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1999-09-01
Project End
2003-07-31
Budget Start
1999-09-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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