Biosynthesis and Function of Lactosaminyl Glycans in Hematopoiesis

乳糖胺聚糖的生物合成及其在造血中的功能

• 批准号: 9277569
• 负责人: ROBERT SACKSTEIN
• 金额: $ 250.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9277569
• 关键词: Address; Adhesives; Anabolism; Blood Platelets; Bone Marrow; Bone Marrow Diseases; Carbohydrates; Cell surface; Cells; Custom; Distal; Future Generations; Glycobiology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhage; Human; Infection; Investigation; Knowledge; Leukocytes; Marrow; Mediating; Medical; Megakaryocytes; Membrane Lipids; Mentors; Modification; Morbidity - disease rate; Mus; Myelopoiesis; Neutropenia; Pathway interactions; Polysaccharides; Process; Proliferating; Proteins; Research; Research Personnel; Resources; Role; Scientist; Secondary to; Shapes; Source; Stem cells; Structure; Surface; Techniques; Therapeutic; Thrombocytopenia; Thrombopoiesis; Training; cancer therapy; chemoradiation; clinically relevant; experimental study; glycosylation; improved; interdisciplinary approach; mortality; progenitor; programs; scaffold; skill acquisition; skills; structural biology; tool

DESCRIPTION (provided by applicant): Infection and bleeding secondary to neutropenia and thrombocytopenia, respectively, are the major causes of near-term morbidity and mortality from chemoradiotherapy. Hematopoietic stem/progenitor cells (HSPCs) proliferate and differentiate in specialized bone marrow microarchitectural domains known as "niches" dictated by critical cell-cell and cell-matrix adhesive interactions. It is well-recognized that expression of sialyl and/or fucosyl modifications of terminal lactosaminyl glycans (i.e., at distal end of carbohydrate chains attached to protein or lipid of the cell membrane) mediate and/or modulate multiple adhesive interactions. The central hypothesis of this proposal is that these cell surface glycans critically shape formation of marrow niches that sustain HSPCs and dictate lineage fate decisions. Specifically, we wish to elucidate the role(s) of terminal lactosaminyl glycans in regulating myelopoietic and thrombopoletic processes. We seek to obtain fundamental information regarding the stage- and lineage-specific distribution of terminal lactosaminyl glycans on pertinent scaffolds of relevant progenitor cells and the biosynthetic pathway(s) that direct their expression, their structural biology (linkages and branching/multiplicity), their influence(s) on marrow adhesive interactions, and, altogether, their effect(s) on clonogenicity. This program proposal employs a multidisciplinary approach to address these central issues, offering synergistic structure-function studies integrated into three interwoven projects: Project 1 (Sackstein) will use primary human HSPCs derived from clinically-relevant sources to elucidate the temporospatial expression and function of terminal lactosaminyl glycans in early hematopoietic and myelopoietic cells, and will develop strategies to remodel surface lactosaminyl glycans; Project 2 (Lau) will investigate human and mouse HSPCs to identify the biosynthetic pathways that direct stage-specific expression of terminal lactosaminyl glycans; Project 3 (Hoffmeister) will study mouse and human megakaryocyte progenitors and megakaryocytes to define the temporal changes and function(s) of terminal lactosaminyl glycans during thrombopoiesis, and will analyze the role(s) of platelets in mediating extrinsic glycosylation pathways. Moreover, this program will establish new technical resources to interrogate glycan structure and function, and will establish a glycosciences skills development core that will provide training in the background, tools and techniques necessary for the creation of new investigators possessing the requisite knowledge and skills to drive forward the field of translational glycobiology. Thus, it is anticipated that the experiments and approaches proposed in this program will address key questions in glycobiology and in hematopoiesis enabling transformative therapeutic strategies to custom-modify surface glycans to optimize myelopoiesis and thrombopoiesis, will expand glycan analytical resources, and will also fundamentally serve to mentor/nurture the future generation(s) of scientists required to undertake investigations at the interface of glycoscience and medical necessity. RELEVANCE: Deficiency in white cells and platelets is associated with cancer treatment, and also occurs in bone marrow diseases. This research effort should yield new treatments to improve marrow function in such conditions. (End of Abstract)

描述（由申请人提供）：分别是中性粒细胞减少症和血小板减少症的感染和出血，是化学上治疗近期发病率和死亡率的主要原因。造血干/祖细胞（HSPC）在专门的骨髓微构造域增殖并区分被关键细胞 - 细胞和细胞矩阵粘合剂相互作用所决定的称为“小甲基”。众所周知，末端乳糖酰糖基甘氨酸糖（即，在连接到细胞膜的蛋白质或脂质的碳水化合物链的远端）的siAlyl和/或岩藻糖基修饰的表达介导并调节多种粘合剂相互作用。该提议的中心假设是这些细胞表面糖果批判性地塑造了骨髓壁ni的形成，该牙髓是维持HSPC并决定血统命运决定的。具体而言，我们希望阐明末端乳糖胺基糖在调节骨髓和血栓性过程中的作用。我们寻求获取有关末端乳糖胺基聚糖在相关祖细胞的相关支架上以及指导其表达，其结构生物学（链接和分支/多重性），他们的结构生物学（其结构性和分支）的相关支架上的末端和谱系特异性分布的基本信息（s）对骨髓粘合剂相互作用的影响，以及它们对克隆性的影响。该计划提案采用多学科方法来解决这些核心问题，提供结构性结构 - 功能研究研究，整合到三个交织的项目中：项目1（萨克斯坦）将使用源自临床上与临床相关的原始来源得出的主要人类HSPC来阐明终端的临时表达和功能早期造血和骨髓细胞中的乳糖胺基聚糖，并将制定重塑表面乳糖胺基聚糖的策略；项目2（LAU）将研究人类和小鼠HSPC，以识别直接乳糖胺基聚糖的特异性表达的生物合成途径；项目3（Hoffmeister）将研究小鼠和人类的巨核细胞祖细胞和巨核细胞，以定义血小板过程中末端乳糖胺基聚糖的时间变化和功能，并将分析血小板在介导外糖糖基糖基化路径中的血小板作用。此外，该计划将建立新的技术资源来询问聚糖的结构和功能，并建立糖基镜技能开发核心，该核心将在背景，工具和技术中提供培训，以创建拥有具有必要知识和技能的新调查人员，以推动推动的知识和技能转发转化性糖生物学领域。因此，预计该计划中提出的实验和方法将解决糖生物学和造血中的关键问题，从而实现可转化的治疗策略，以自定义地表聚糖，以优化骨髓骨髓和血栓形成，并将扩展Glycan分析资源，并将提供基本的分析资源，并将提供基本的分析资源，并将提供基础。指导/培育在糖科和医疗必要性界面进行调查的科学家的未来一代。相关性：白细胞和血小板的缺乏与癌症治疗有关，也发生在骨髓疾病中。这项研究工作应产生新的治疗方法，以在这种情况下改善骨髓功能。 （抽象的结尾）

项目成果

Hitting the sweet spot for lymphoma.

达到治疗淋巴瘤的最佳效果。

• DOI: 10.1182/blood-2010-03-272955
• 发表时间: 2010
• 期刊: Blood
• 影响因子: 20.3
• 作者: Sackstein,Robert

Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression.

• DOI: 10.1038/s41598-017-17981-z
• 发表时间: 2018-01-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Donnelly C;Dykstra B;Mondal N;Huang J;Kaskow BJ;Griffin R;Sackstein R;Baecher-Allan C
• 通讯作者: Baecher-Allan C

A Glycovariant of Human CD44 is Characteristically Expressed on Human Mesenchymal Stem Cells.

• DOI: 10.1002/stem.2549
• 发表时间: 2017-04
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Pachón-Peña G;Donnelly C;Ruiz-Cañada C;Katz A;Fernández-Veledo S;Vendrell J;Sackstein R
• 通讯作者: Sackstein R

Multi-level regulation of cellular glycosylation: from genes to transcript to enzyme to structure.

• DOI: 10.1016/j.sbi.2016.09.013
• 发表时间: 2016-10
• 期刊: CURRENT OPINION IN STRUCTURAL BIOLOGY
• 影响因子: 6.8
• 作者: Neelamegham, Sriram;Mahal, Lara K.
• 通讯作者: Mahal, Lara K.

Crystallization, preliminary X-ray crystallographic and cryo-electron microscopy analysis of a bifunctional enzyme fucokinase/L-fucose-1-P-guanylyltransferase from Bacteroides fragilis.

• DOI: 10.1107/s2053230x14012722
• 发表时间: 2014-09
• 期刊: Acta crystallographica. Section F, Structural biology communications
• 作者: Chongyun Cheng;J. Gu;Jing Su;W. Ding;Jie Yin;W. Liang;Xiaoxia Yu;Jun Ma;P. Wang;Zhi-Cheng Xiao;Zhi-jie Liu