Glycan Modulation of Inflammatory Responses

描述（由申请人提供）：我们建议使用转基因小鼠和细菌合作研究聚糖调节炎症反应，涉及骨髓细胞，内皮生物学，先天免疫和宿主-微生物相互作用。特别关注的是两种主要阴离子聚糖的作用：唾液酸（Sias）和糖胺聚糖（GAGs），透明质酸（HA），硫酸肝素（HS）和硫酸软骨素/硫酸皮肤素（CS/DS）。特异的聚糖结合蛋白区别地识别这些聚糖，介导炎症中的许多重要功能。这些聚糖的许多生理和病理作用在培养细胞中并不完全明显，其中一些如在炎症中的作用必须在完整的脊椎动物中探索。这种聚乙二醇的潜在主题是最先进的基因操作这些聚糖，和/或其同源结合蛋白在小鼠。我们高度互动的专家团队得到最先进的核心设施的支持，有许多智力和实际合作和协同作用的机会。项目1将阐明激活和arg突变形式的cd33相关Siglecs在髓细胞上的功能，这可能代表了对表达Sias的病原体的进化调整。项目2将研究骨髓细胞受到微生物挑战时的先天免疫功能，这些微生物要么模仿宿主Sias或GAGs，要么产生靶向它们的糖苷酶。项目3研究HS和CS/DS链的硫酸化模式在调节髓细胞和内皮生物学中的作用。项目4研究在炎症过程中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PEG的研究和培训目标：核心A，用于招募和培训研究员的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，行政与鼠标管理核心；核心D，组织病理学；核心E，血液学和临床化学。总体目标是了解Sias和GAGs在炎症生物学中的多方面作用，增加糖科学资源，并确定和培养具有强大潜力的优秀博士后，成为NHLBI相关领域的杰出独立研究者。

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.