Project 2: Extracellular Glycosylation and Blood Cell Production

项目2：细胞外糖基化和血细胞生产

• 批准号: 10321581
• 负责人: Joseph TY Lau
• 金额: $ 54.89万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321581
• 关键词: Affect; Attenuated; Automobile Driving; B-Lymphocytes; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Diseases; Catalysis; Cell Maintenance; Cell surface; Cells; Characteristics; Clinical; Collaborations; Cues; DNA Sequence Alteration; Data; Development; Disease; Dysmyelopoietic Syndromes; Dysplastic Megakaryocyte; Environment; Extracellular Matrix; Generations; Genetic; Glycobiology; Glycosaminoglycans; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Homeostasis; Interphase; Investigation; Lesion; Life; Ligands; Maintenance; Marrow; Mediating; Megakaryocytes; Modality; Molecular; Myelogenous; Myeloid Cells; Myeloproliferative disease; Patients; Physiological; Platelet Count measurement; Polysaccharides; Process; Production; Regulation; Residencies; Role; Selectins; Sialic Acids; Sialyltransferases; Signal Transduction; Source; Specificity; Syndrome; Testing; Therapeutic; Time Study; Transferase; Work; clinical diagnostics; diagnostic strategy; driver mutation; extracellular; glycosylation; glycosyltransferase; hematopoietic differentiation; mimetics; mouse model; novel; novel diagnostics; novel therapeutics; platelet function; programs; sialyl Lewis x; sialylation; therapeutic development; transcriptomics

Project 2 – Project Summary Maintaining hematopoiesis is critical for life. Generating the proper numbers of functional blood cells across all lineages requires cell-intrinsic developmental programs, but these programs require guidance from cell-extrinsic mechanisms that correctly convey the physiologic needs for these cells. Glycans on the cell surface and in the extracellular milieu reside at the interphase through which the cell-extrinsic cues are conveyed. The overarching Program Hypothesis is that cell-intrinsic and extrinsic glycan-mediated mechanisms regulate maintenance, differentiation, and function of hematopoietic cells. Glycosyltransferases such as the sialyltransferase ST6GAL1 are also residents of the extracellular milieu. Our preliminary data point to a role for the extracellular, or extrinsic ST6GAL1, and possibly other glycosyltransferases in the marrow to influence hematopoietic decisions on multiple levels of blood cell development. Outside of the marrow, platelets upon activation release the sialic acid donor substrate required to drive extrinsic sialyltransferase catalysis. Together with Project 1, we will explore the idea that megakaryocytes, the precursors of platelets, control marrow extrinsic sialylation by a similar mechanism. Together with Project 3, we have uncovered a totally unexpected interaction between glycosaminoglycan components of the extracellular matrix with ST6GAL1, and we have identified a number of GAG-mimetics with striking ability to modulate extrinsic ST6GAL1 sialylation on target cells. Disturbed hematopoiesis with highly heterogenous presentation and varied underlying driver mutations is the defining hallmark of clonal myeloid diseases such as myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS). However, a key common feature of MPN and MDS is dysplastic megakaryocytes with altered circulating platelet numbers and function. Our preliminary data point to distinct glycosylation signatures associated with platelets from patients of these diseases, suggesting fundamental alterations to the bone marrow environment and the megakaryocytes that produce the platelets. We hypothesize that glycosylation, especially extrinsic glycosylation, regulates blood cell homeostasis, ultimately impacting the number and function of circulating blood cells in health and in disease. We will test this hypothesis in three Specific Aims to 1) understand how extrinsic ST6GAL1 regulates HSPC maintenance; 2) understand how extrinsic sialylation in the marrow is regulated; and 3) initiate a first-time study on how glycosylation is modified in clinical MDS and MPN and in mouse models. The proposed study is expected to yield transformative understanding of extrinsic glycosylation in cell-niche interactions critical to maintaining blood cell production. This is also a pioneering investigation into the glycoscience of clinical MDS and MPN, with potential for novel therapeutics and diagnostics.

项目2 - 项目摘要 维持造血对生命至关重要。在所有人中生成适当数量的功能性血细胞 谱系需要细胞中的开发程序，但是这些程序需要细胞超级指导 正确传达这些细胞生理需求的机制。在细胞表面和 细胞外环境位于传达细胞超支线索的相间。总体 程序假设是细胞中性和外部聚糖介导的机制调节维护， 造血细胞的分化和功能。 糖基转移酶（例如辅酶基转移酶ST6GAL1）也是细胞外环境的居民。我们的 初步数据指出了细胞外或外部ST6GAL1的作用，甚至可能 骨髓中的糖基转移酶在多个水平的血细胞上影响造血决定 发展。在骨髓外，血小板激活后释放唾液酸供体底物需要 与项目1一起，我们将探讨这样的想法 巨核细胞是血小板的前体，通过类似的机制来控制骨髓外部溶解。 与项目3一起，我们发现了糖胺聚糖之间完全意外的互动 具有ST6GAL1的细胞外矩阵的组件，我们已经确定了许多GAG-MIMETICS 在靶细胞上调节外在的ST6GAL1溶解度的惊人能力。 具有高度异质表现和不同基础驱动突变的造血障碍是 定义克隆髓样疾病的标志，例如骨髓增生性肿瘤（MPN）和骨髓增生性 综合征（MDS）。但是，MPN和MD的关键共同特征是变化的巨核细胞发育不良 循环血小板数和功能。我们的初步数据指向不同的糖基化特征 与这些疾病患者的血小板有关，表明对骨髓的基本改变 产生血小板的环境和巨核细胞。我们假设糖基化，尤其是 除外糖基化，调节血细胞稳态，最终影响 健康和疾病中的血细胞循环。我们将以三个特定目的来检验这一假设1） 外部ST6GAL1如何调节HSPC维护； 2）了解骨髓中的外部溶酶是如何 受监管； 3）首次研究如何在临床MDS和MPN中修改糖基化以及在 鼠标模型。拟议的研究预计将对外部糖基化产生变革性的理解 在维持血细胞产生至关重要的细胞基属相互作用中。这也是对 临床MDS和MPN的糖性具有新的治疗和诊断潜力。