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Structure/Function of Surfactant Protein D

表面活性剂蛋白 D 的结构/功能

基本信息

批准号：
7099573
负责人：
ERIKA Christine CROUCH
金额：
$ 37.35万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-01-01 至 2009-07-31
项目状态：
已结题

项目摘要

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.

描述(由申请人提供)：表面活性蛋白D(SP-D)是一种由肺泡II型和细支气管上皮细胞分泌的胶原性碳水化合物结合蛋白(集合素)。SP-D在机体对微生物的先天防御中发挥重要作用，并参与肺对抗原攻击的应答。它是一种模式识别分子，具有多种配体，包括微生物糖结合物和有机抗原。这些相互作用的结果是多种多样的，包括微生物凝集、调理作用、抑制T淋巴细胞增殖、调节白细胞功能和增强抗原呈递。SP-D的模式识别能力是在多个结构层次上确定的。虽然每个单体都含有一个凝集素结构域(CRD)，但SP-D是以三聚体亚基的寡聚体形式组装在它们的N-肽中的。三聚体CRD的形成是高亲和力配体结合的关键，CRD在三聚体中的空间分布有助于配体的特异性。然而，三聚体亚基的寡聚化是桥联相互作用和许多生物活性所必需的。虽然SP-D优先形成十二聚体，但更大的多聚体和三聚体在体内积累，比例可能会随着疾病的背景而改变。尽管寡聚对SP-D的功能很重要，但人们对多聚化的结构决定因素或调节组装和分泌的细胞机制知之甚少。因此，我们提出了四个目标：1)进一步表征链结合和交联所需的N-肽的结构特征；2)表征胶原、Neck和CRD在SP-D单体三聚化和高阶低聚物组装中的作用；3)进一步确定SP-D高效分泌所必需的结构特征；以及4)表征调控SP-D组装和分泌的细胞机制，重点是特定的伴侣。这些研究将提供与集合素生物合成相关的新的机制信息，并将为理解遗传多态、突变和获得性变异在集合素组装中的潜在后果提供基础。它们还将有助于我们努力开发具有独特生物学特性的新型收集素，这些收集素可用于增强宿主防御或调节肺部的炎症和免疫反应。与过去一样，具有新结构属性的分泌型重组蛋白将被表征并用于SP-D功能的协作研究。

项目成果

期刊论文数量（55）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effect of lung surfactant collectins on bronchoalveolar macrophage interaction with Blastomyces dermatitidis: inhibition of tumor necrosis factor alpha production by surfactant protein D.

肺表面活性剂集合素对支气管肺泡巨噬细胞与皮炎芽生菌相互作用的影响：表面活性剂蛋白 D 抑制肿瘤坏死因子 α 的产生。

DOI：
10.1128/iai.00243-06
发表时间：
2006
期刊：
Infection and immunity.
影响因子：
0
作者：
Lekkala,Madhavi;LeVine,AnnMarie;Linke,MichaelJ;Crouch,ErikaC;Linders,Bruce;Brummer,Elmer;Stevens,DavidA
通讯作者：
Stevens,DavidA

Recognition of mannosylated ligands and influenza A virus by human surfactant protein D: contributions of an extended site and residue 343.

DOI：
10.1021/bi8022703
发表时间：
2009-04-21
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Crouch, Erika;Hartshorn, Kevan;Horlacher, Tim;McDonald, Barbara;Smith, Kelly;Cafarella, Tanya;Seaton, Barbara;Seeberger, Peter H.;Head, James
通讯作者：
Head, James

Modulation of surfactant protein D expression by glucocorticoids in fetal rat lung.

糖皮质激素对胎鼠肺表面活性蛋白 D 表达的调节。