Project 2: Extracellular Glycosylation and Blood Cell Production

项目2：细胞外糖基化和血细胞生产

基本信息

批准号：
10545016
负责人：
Joseph TY Lau
金额：
$ 60.99万
依托单位：
VERSITI WISCONSIN, INC.
依托单位国家：
美国
项目类别：
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/10545016
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 Disparate 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 Myelodysplastic/Myeloproliferative Disease Myelogenous Myeloid Cells Myeloproliferative disease Neoplasms Patients Physiological Platelet Count measurement Polysaccharides Process Production Regulation Residencies Role Selectins Sialic Acids Sialyltransferases Signal Transduction Source Specificity Syndrome Testing Therapeutic Time Study 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

项目摘要

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 – 项目概要维持造血功能对于生命来说至关重要。谱系需要细胞内在的发育程序，但这些程序需要细胞外在的指导正确传达细胞表面和细胞内的聚糖的生理需求的机制。细胞外环境存在于细胞间期，通过它传递细胞外在信号。程序假设是细胞内在和外在聚糖介导的机制调节维持，造血细胞的分化和功能。糖基转移酶（例如唾液酸转移酶 ST6GAL1）也是细胞外环境的居民。初步数据表明细胞外或外源性 ST6GAL1 以及可能的其他因素的作用骨髓中的糖基转移酶影响血细胞多个水平的造血决策在骨髓外，血小板激活后释放所需的唾液酸供体底物。为了驱动外源性唾液酸转移酶催化，我们将与项目 1 一起探索以下想法：巨核细胞是血小板的前体，通过类似的机制控制骨髓外源性唾液酸化。与项目 3 一起，我们发现了糖胺聚糖之间完全意想不到的相互作用 ST6GAL1 是细胞外基质的组成部分，我们已经鉴定出许多 GAG 模拟物调节靶细胞外源性 ST6GAL1 唾液酸化的能力惊人。具有高度异质性表现和各种潜在驱动突变的造血功能紊乱是克隆性骨髓疾病的定义标志，例如骨髓增生性肿瘤（MPN）和骨髓增生异常然而，MPN 和 MDS 的一个重要共同特征是巨核细胞发育异常。我们的初步数据表明了不同的糖基化特征。与这些疾病患者的血小板有关，表明骨髓发生了根本性改变我们勇敢地面对糖基化，尤其是环境和产生血小板的巨核细胞。外源糖基化，调节血细胞稳态，最终影响细胞的数量和功能我们将通过三个具体目标来检验这一假设：1) 理解健康和疾病中的循环血细胞。外源性 ST6GAL1 如何调节 HSPC 维持；2) 了解骨髓中外源性唾液酸化的作用； 3) 启动首次研究糖基化在临床 MDS 和 MPN 以及拟议的研究有望产生对外源糖基化的变革性理解。对维持血细胞产生至关重要的细胞生态位相互作用，这也是一项开创性的研究。临床 MDS 和 MPN 的糖科学，具有新型治疗和诊断的潜力。