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.
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