Surfactant Protein D (SP-D) is a collagenous carbohydrate binding protein that is secreted into the airspaces of the lung by type II and nonciliated bronchiolar epithelial cells. SP-D binds to glycoconjugates expressed on various microorganisms and particulate antigens, can modulate the activities of inflammatory cells, and may also contribute to the metabolism of lung surfactant. SP-D production increases following lung injury consistent with its participation in the pulmonary """"""""acute phase response"""""""" (APR). For these reasons, it is important to understand the mechanisms that regulate the expression of SP-D and its accumulation in the airspace. Our studies have shown that the assembly of trimeric subunits and the formation of dodecamers or larger multimers is important- if not critical- for many of it's activities. In addition, our studies of the human gene have lead to the identification of a conserved AP-1 element (-109) and a functional C/EBP-like protein binding sequence (-340) that could contribute to basal expression and the increased expression of SP-D following lung injury. Accordingly. we propose four aims. First, we plan to further characterize the proximal promoter with emphasis on the conserved sequences that flank the AP-1 element, including a downstream HNF-3 binding site and an upstream binding site that includes overlapping E-Box, GT- box and GATA-like motifs. Second, we will further characterize the putative C/EBP element at -340 and a tandem motif at -319, and examine the contribution of other C/EBP motifs and potential STAT binding sequences. We will also examine potential modulatory effects of retinoblastoma protein and glucocorticoids on C/EBP- mediated transcriptional activation, and the regulatory activities of IL-6 and other cytokines and hormones previously implicated in the regulation of the hepatic APR. Third, we propose to characterize a recently identified untranslated exon within """"""""intron 1"""""""" of the human gene. Fourth, we propose to continue with studies examining the mechanisms of SP-D trimerization, multimerization, and secretion of SP-D. Our ongoing and proposed studies will provide important information related to the regulation of SP-D production, the assembly of functional multimers, and the response of the lung to microbial challenge and other forms of lung injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044015-13
Application #
6536967
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Gail, Dorothy
Project Start
1990-01-01
Project End
2003-07-31
Budget Start
2002-06-01
Budget End
2003-07-31
Support Year
13
Fiscal Year
2002
Total Cost
$311,125
Indirect Cost
Name
Barnes-Jewish Hospital
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Crouch, Erika C; Hirche, Tim O; Shao, Baohai et al. (2010) Myeloperoxidase-dependent inactivation of surfactant protein D in vitro and in vivo. J Biol Chem 285:16757-70
Crouch, Erika; Hartshorn, Kevan; Horlacher, Tim et al. (2009) Recognition of mannosylated ligands and influenza A virus by human surfactant protein D: contributions of an extended site and residue 343. Biochemistry 48:3335-45
Matalon, Sadis; Shrestha, Kedar; Kirk, Marion et al. (2009) Modification of surfactant protein D by reactive oxygen-nitrogen intermediates is accompanied by loss of aggregating activity, in vitro and in vivo. FASEB J 23:1415-30
Carlson, Tracy K; Torrelles, Jordi B; Smith, Kelly et al. (2009) Critical role of amino acid position 343 of surfactant protein-D in the selective binding of glycolipids from Mycobacterium tuberculosis. Glycobiology 19:1473-84
White, Mitchell; Kingma, Paul; Tecle, Tesfaldet et al. (2008) Multimerization of surfactant protein D, but not its collagen domain, is required for antiviral and opsonic activities related to influenza virus. J Immunol 181:7936-43
Hartshorn, Kevan L; Webby, Richard; White, Mitchell R et al. (2008) Role of viral hemagglutinin glycosylation in anti-influenza activities of recombinant surfactant protein D. Respir Res 9:65
Wang, Lin; Brauner, Joseph W; Mao, Guangru et al. (2008) Interaction of recombinant surfactant protein D with lipopolysaccharide: conformation and orientation of bound protein by IRRAS and simulations. Biochemistry 47:8103-13
Wang, Hua; Head, James; Kosma, Paul et al. (2008) Recognition of heptoses and the inner core of bacterial lipopolysaccharides by surfactant protein d. Biochemistry 47:710-20
Reading, Patrick C; Bozza, Silvia; Gilbertson, Brad et al. (2008) Antiviral activity of the long chain pentraxin PTX3 against influenza viruses. J Immunol 180:3391-8
Cooley, Jessica; McDonald, Barbara; Accurso, Frank J et al. (2008) Patterns of neutrophil serine protease-dependent cleavage of surfactant protein D in inflammatory lung disease. J Leukoc Biol 83:946-55

Showing the most recent 10 out of 68 publications