Glycan Modulation of Inflammatory Responses

炎症反应的聚糖调节

基本信息

批准号：
8792031
负责人：
AJIT P VARKI
金额：
$ 8.53万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8792031
关键词：
Accounting Address Area Bacteria Binding Proteins Biological Biology Blood Blood Cells Caenorhabditis elegans Cardiovascular system Catabolism Cells Clinical Chemistry Collaborations Complex Core Facility Cultured Cells Development Discipline Disease Education Embryo Endothelial Cells Future Genetic Glycosaminoglycans Glycoside Hydrolases Goals Health Heart Hematology Hematopoiesis Heparitin Sulfate Histopathology Human Hyaluronan Immune response Immune system Immunity In Vitro Inflammation Inflammatory Response Invertebrates Investigation Knowledge Lung Mammals Mediating Microbe Mission Modeling Morphologic artifacts Mus Mutate Myeloid Cells National Heart, Lung, and Blood Institute Natural Immunity Nucleic Acids Oligosaccharides Organism Pattern Phenotype Physiological Plasma Proteins Polysaccharides Postdoctoral Fellow Proteins Reporting Research Research Personnel Research Project Grants Research Training Resource Sharing Resources Role Sampling Studies Scientist Sialic Acids System Technology Testing Time Tissues Training Variant Vascular Endothelium Vascular System Work cell type dermatan sulfate chondroitin sulfate genetic manipulation glycosylation innate immune function interest macrophage microorganism interaction monocyte multidisciplinary neutrophil pathogen programs sialic acid binding Ig-like lectin skills sugar sulfation

项目摘要

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.

描述（由申请人提供）：我们建议使用转基因小鼠和细菌对聚糖调节炎症反应进行合作研究，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。特别关注两种主要类型阴离子聚糖的作用：唾液酸 (Sias) 和糖胺聚糖 (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)。特定的聚糖结合蛋白差异性地识别这些聚糖，介导炎症中的许多重要功能。此类聚糖的许多生理和病理作用在培养细胞中并不完全明显，并且必须在完整的脊椎动物中探索某些聚糖在炎症中的作用。该 PEG 的一个基本主题是对小鼠中这些聚糖和/或其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最先进的核心设施的支持，并提供许多智力和实践合作与协同的机会。项目 1 将阐明骨髓细胞上 CD33 相关 Siglecs 的激活形式和 Arg 突变形式的功能，这可能代表表达 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的先天免疫功能，这些微生物要么模仿宿主 Sias 或 GAG，要么产生针对它们的糖苷酶。项目 3 研究 HS 和 CS/DS 链在调节骨髓细胞和内皮生物学中的硫酸化模式。项目 4 研究 HA 分解代谢如何在炎症过程中发挥作用来调节先天免疫反应。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； Core B，用于聚糖合成和分析的共享资源；核心C，行政和鼠标管理核心；核心 D，组织病理学；和核心 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，增强糖科学的资源，并识别和培训最优秀的博士后研究员，他们有强大的潜力发展成为该领域的杰出独立研究人员与 NHLBI 相关。