Structure/Function of Surfactant Protein D

描述（由申请人提供）：

DESCRIPTION (provided by applicant): Surfactant Protein D (SP-D) is a collagenous carbohydrate binding protein (collectin) that is secreted by alveolar type II and bronchiolar epithelial cells. SP-D plays important roles in the innate defense against microorganisms and contributes to the lung's response to antigenic challenge. It is a pattern recognition molecule with a variety of ligands including microbial glycoconjugates and organic antigens. The consequences of these interactions are diverse and include microbial agglutination, opsonization, inhibition of T-lymphocyte proliferation, modulation of leukocyte function, and enhanced antigen presentation. The pattern recognition capacities of SP-D are determined at several levels of structure. Although each monomer contains a single lectin domain (CRD), SP-D is assembled as oligomers of trimeric subunits cross-linked within their N-peptides. The formation of trimeric CRDs is critical for high affinity ligand binding, and the spatial distribution of CRDs within the trimer contributes to ligand specificity. However, oligomerization of trimeric subunits is required for bridging interactions and many biological activities. Although SP-D preferentially forms dodecamers, larger multimers and trimers accumulate in vivo, and the proportions can change in the setting of disease. Despite the importance of oligomerization for SP-D function, little is known about the structural determinants of multimerization or the cellular mechanisms that regulate assembly and secretion. Accordingly, we propose four aims: 1) to further characterize the structural features of the N-peptide required for chain association and cross-linking; 2) to characterize the contributions of the collagen, neck, and CRDs to the trimerization of SP-D monomers and the assembly of higher order oligomers; 3) to further define the structural features of SP-D that are necessary for efficient cellular secretion; and 4) to characterize the cellular mechanisms regulating SP-D assembly and secretion with emphasis on specific chaperones. These studies will provide new and mechanistic information relating to collectin biosynthesis, and will provide a basis for understanding the potential consequences of genetic polymorphisms, mutations, and acquired variations in collectin assembly. They will also facilitate our efforts to develop novel collectins with unique biological properties that can be used to augment host defenses or modulate inflammatory and immune reactions in the lung. As in the past, secreted recombinant proteins with novel structural attributes will be characterized and utilized for collaborative studies of SP-D function.