Glycan Modulation of Inflammatory Responses

描述(申请人提供)：我们建议使用转基因小鼠和细菌，合作研究涉及髓系细胞、内皮生物学、先天免疫和宿主-微生物相互作用的炎症反应的葡聚糖调控。特别关注两种主要类型的阴离子多聚糖的作用：唾液酸(SIAS)和糖胺多聚糖(GAG)、透明质酸(HA)、硫酸乙酰肝素(HS)和硫酸软骨素/硫酸皮肤素(CS/DS)。特定的糖链结合蛋白识别这些糖链，在炎症中起着重要的调节作用。这种多糖的许多生理和病理作用在培养细胞中并不完全明显，一些作用，如在炎症中的作用，必须在完整的脊椎动物中进行探索。这种聚乙二醇组分的一个基本主题是在小鼠体内对这些多糖和/或它们的同源结合蛋白进行最先进的遗传操作。我们高度互动的专家团队得到了最先进的核心设施的支持，为智力和实际合作和协同提供了许多机会。项目1将阐明活化和Arg突变形式的CD33相关Siglecs在髓系细胞上的功能，这可能代表着对表达SIAs的病原体的进化调整。项目2将研究髓系细胞的先天免疫功能，这些细胞受到模拟宿主SIAs或GAG的微生物的挑战，或者产生针对它们的糖苷酶。项目3研究HS和CS/DS链在调节髓系细胞和内皮生物学中的硫酸盐化模式。项目4研究了炎症过程中HA分解代谢如何调节先天免疫反应。我们提出了五个核心来支持聚乙二醇组的研究和培训目标：核心A，用于招募和培训研究员的血糖科学技能发展核心；核心B，多糖合成和分析的共享资源；核心C，管理和老鼠管理核心；核心D，组织病理学；以及核心E，血液学和临床化学。总体目标是了解SIAs和GAG在炎症生物学中的多方面作用，增加血糖科学的资源，并确定和培训最好的博士后研究员，他们有很强的潜力发展为在NHLBI相关领域工作的杰出独立研究人员。

DESCRIPTION (provided by applicant): We propose collaborative studies of glycan modulation of inflammatory responses involving myeloid cells, endothelial biology, innate immunity and host-microbial interactions - using genetically-modified mice and bacteria. A particular focus is on roles of two major types of anionic glycans: sialic acids (Sias) and the glycosaminoglycans (GAGs), hyaluronan (HA), heparan sulfate (HS) and chondroitin sulfate/dermatan sulfate (CS/DS). Specific glycan-binding proteins differentially recognize these glycans, mediating many important functions in inflammation. Many physiologic and pathological roles of such glycans are not fully evident in cultured cells, and some such as roles in inflammation must be explored in an intact vertebrate. An underlying theme of this PEG is state-of-the-art genetic manipulation of these glycans, and/or their cognate binding proteins in the mouse. Our highly interactive team of experts is support by state-of-the-art Core facilities with many opportunities for intellectual and practical collaborations and synergies. Project 1 will elucidate functions of activatory and Arg-mutated forms of CD33-related Siglecs on myeloid cells, which likely represent evolutionary adjustments to pathogens expressing Sias. Project 2 will study innate immune functions of myeloid cells challenged by microbes that either mimic host Sias or GAGs, or which produce glycosidases targeting them. Project 3 studies sulfation patterns of HS and CS/DS chains in regulating myeloid cells and endothelial biology. Project 4 investigates how HA catabolism acts during inflammation to modulate the innate immune response. We proposed five cores to support the research and training objectives ofthe PEG: Core A, a Glycosciences Skills Development Core for recruitment and training of Fellows; Core B, a shared resource for Glycan Synthesis and Analysis; Core C, Administrative and Mouse Management Core; Core D, Histopathology; and Core E, Hematology and Clinical Chemistry. The overall objective is to understand the multi-faceted roles of Sias and GAGs in the biology of inflammation, enhance resources for glycosciences, and to identify and train the best postdoctoral fellows who have a strong potential to develop into an outstanding independent investigators working in areas relevant to NHLBI.