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: 8669077
• 负责人: ROBERT SACKSTEIN
• 金额: $ 243.89万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8669077
• 关键词: Address; Adhesives; Anabolism; Blood Platelets; Bone Marrow; Bone Marrow Diseases; Carbohydrates; Cell surface; Cells; Custom; Development; Distal; Future Generations; Glycobiology; Hematopoiesis; Hematopoietic; 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; Staging; Stem cells; Structure; Surface; Techniques; Therapeutic; Thrombocytopenia; Thrombopoiesis; Training; abstracting; cancer therapy; chemoradiation; clinically relevant; glycosylation; improved; interdisciplinary approach; mortality; progenitor; programs; research study; scaffold; skills; stem; 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）：中性粒细胞减少症和血小板减少症继发的感染和出血分别是放化疗近期发病率和死亡率的主要原因。造血干/祖细胞（HSPC）增殖和分化的专门的骨髓微结构域称为“壁龛”决定的关键细胞-细胞和细胞-基质粘附相互作用。众所周知，末端乳糖胺聚糖的唾液酸和/或岩藻糖基修饰的表达（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）介导和/或调节多种粘附相互作用。这一提议的中心假设是，这些细胞表面聚糖对维持HSPC并决定谱系命运决定的骨髓小生境的形成具有重要影响。具体而言，我们希望阐明末端乳糖胺聚糖在调节骨髓和血栓形成过程中的作用。我们试图获得有关相关祖细胞相关支架上末端乳糖胺聚糖的阶段和谱系特异性分布以及指导其表达的生物合成途径、其结构生物学（连接和分支/多样性）、其对骨髓粘附相互作用的影响以及其对克隆形成的影响的基本信息。该计划建议采用多学科方法来解决这些核心问题，提供整合到三个相互交织的项目中的协同结构-功能研究：（Sackstein）将使用来自临床相关来源的原代人HSPC来阐明早期造血和骨髓细胞中末端乳糖胺聚糖的时空表达和功能，并将开发重塑表面乳糖胺聚糖的策略;项目2（Lau）将研究人和小鼠HSPC，以确定指导末端乳糖胺聚糖阶段特异性表达的生物合成途径;项目3（Hoffmeister）将研究小鼠和人巨核细胞祖细胞和巨核细胞，以确定血小板生成期间末端乳糖胺聚糖的时间变化和功能，并将分析血小板在介导外源性糖基化途径中的作用。此外，该计划将建立新的技术资源来询问聚糖结构和功能，并将建立一个糖科学技能发展核心，该核心将提供背景，工具和必要的技术培训，以创建拥有必要知识和技能的新研究人员，以推动翻译糖生物学领域的发展。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，从而实现变革性治疗策略，以定制修饰表面聚糖，以优化骨髓生成和血小板生成，将扩大聚糖分析资源，也将从根本上指导/培养下一代需要科学家在糖科学和医疗必要性的界面进行调查。相关性：白色细胞和血小板缺乏与癌症治疗有关，也发生在骨髓疾病中。这项研究工作应该产生新的治疗方法，以改善这种情况下的骨髓功能。(End摘要）